LADME=what does the body do to the drug? = Pharmacokinetics
Lecture 1 Pharmacodynamics =what does the drug do to the body ~Pharmacological effects ~Physiological effects
Pharmacokinetics in your life What happens to a drug after its administration? A young child given an IM injection might ask : "How will that 'ouch' get from there to my sore throat"? LADME D 1. Liberation =releasing The answer to this question is the basis of 2. Absorption pharmacokinetics, i. e., how drugs move around the body A M and how quickly this movement occurs. E 3. Distribution During this semester many of the processes which control 4. Metabolism the absorption, distribution, metabolism, and excretion of drugs will be discussed. L 5. Excretion
Getting drug from one site to another Disposition of drug in the body
A D
L IV= No A
M E
1 one, two, and three compartment models
Many of the processes involved in drug movement around the body are NOT saturated at normal therapeutic dose levels, making plasma concentration vs. time much simplified
Parameters to be measured in 2 compartment model
Rate for absorption
Two compartment model often has wider application
Common parameters of a blood time curve Therapeutic Range (window, index)
All drugs are poisons Only proper administration determines whether a compound is beneficial or not The amount of drug administered and the resulting concentration in the body determines whether a drug is beneficial or detrimental The ideal range of drug concentrations within the body is referred as Therapeutic range (TR) or therapeutic window or therapeutic index (TI)
2 Therapeutic Range of a drug in Plasma Drug concentration vs. Drug effect
TD50 TI = ED50 So, The larger the TI the ???
Drug entered ~~ Drug leaved Plasma concentrations achieved can be controlled by the rate of drug absorption Dose (absorbed) must match the rate the drug is metabolized + eliminated Absorption too fast, resulting in dosing interval?? Toxic level
TR Sub-therapeutic
1 < 3 3 > 2 3 = 3
The goal of drug therapy: to maintain drug concentration in the TR
Components of therapeutic administration Dose
Unit: mass mg, g (tablet, capsule, mL) Dose: Amount of drugs administered at one time mass/body weight mg/kg, mg/lb (mg/mL)
Loading Dose: Dosage (dosing) Interval: Time between A dose to quickly raise drug conc to therapeutic range. administration of separate drug doses Used in critical condition: ex. life threatening infections, shock
Route of administration: Means by which the drug Maintenance dose: is given Dose required to maintain therapeutic concentration established by loading dose
3 Dosage Interval
What is the difference ??
A. 300 mg s.i.d. Vs. B. 100 mg t.i.d Total Daily dose: Patient compliance: Therapeutic effect: Possible toxicity
Route of administration
Parenteral: beside the intestine
Less fluctuation Intra arterial (IA) Intra vascular (IV) IV Bolus=single large volume IV infusion=slowly dripped over sec, min or hr Larger fluctuation thus overpass toxic level
IV Bolus b = slow release formulation, vs. showed lower peak and IV infusion slower elimination
Think about it! Route of administration-Parenteral
Subcutaneous (SC), Intramuscular (IM) and Intravenous (IV) The difference between IA vs. IV? •Which one is more predictable in distribution? for drugs that are poorly absorbed form the GI tract •Which one is more likely to cause (local) tissue toxicity? for agents that are unstable in the GI tract •Which one is more quickly to effect? •Which one would have higher plasma concentration? ensure active drug absorption more rapid/predictable than oral administration •Hint:
Routes of choice for uncooperative or unconscious patients
4 Route of administration-Enteral Route of administration-Enteral
Oral Rectal Most pharmaceutical companies aim for this –it’s the most convenient and most economical Strategic placement: placement low in rectum, where Factors that determine drug effect following oral veins drain into systemic circulation without passing absorption: through the liver, thus first pass metabolism by the liver Rate & absorption extent by GI tract can thus be bypassed Absorption site (=mainly small intestine, larger surface area) Sublingual Drug ionization state: non-ionized (lipid-soluble) forms are more favorably absorbed Placement under the tongue allows some drugs to diffuse First-Pass Effect into the capillary network and therefore to enter the Drugs absorbed from the GI tract pass through the portal systemic circulation directly, enabling the drug to bypass venous system to the liver, resulting in low systemic the liver and avoid inactivation by hepatic metabolism. circulation due to extensive hepatic metabolism
Route of administration-Others How can drugs be administered Transdermal Allows sustained, therapeutic plasma levels injections Avoids first pass effect Simple and high patient compliance Nasal Route for peptides (degraded by gastric pH if taken orally) and to avoid first pass metabolism Inhalation Choice for anesthetic agents and bronchodilators. (allows for high drug concentrations locally, not systemically). Conjunctival and intrathecal Eye drops and injection into the subarachnoid space via a lumbar puncture needle.
How can drugs be administered How can drugs be administered skin or mucosa skin or mucosa-continued
fentanyl patch
5 Comments on routes of administration Common routes of drug administration Bioavailbility Advantage Disadvantage
Effect of administration routes Effect of administration routes
Administration route affects speed and extent of absorption extentSpeed = = how how high fast drugto reach conc. equilibrium in plasma in can plasma reach No absorption phase=100% absorption I.V. . e c n n
o IM o r c
e Faster absorption and t a s o m higher plasma conc. t s s a e l by IM vs SC SC P T
Movement of Drugs Movement of Drugs Cellular membrane structure
"How does the medicine know where to go".
Drug distribution is directed by the physicochemical properties of the drug and the physiology of the body membranes and fluids.
6 Absorption mechanisms- passive diffusion Passive diffusion
Does not involve a carrier, is not saturable, shows low structural Prerequisite: Drug has to be in solution specificity Passive diffusion Fick’s Law describes passive movement down concentration gradient The mechanism by which the majority of drugs gain access to the body Facilitate transport Water-soluble drugs penetrate the cell through aqueous channels Active transport Charged drugs will be influenced by membrane potentials Convective transport Lipid-soluble drugs readily move across most biological membranes Ion-pair transport Factors affecting the Passive diffusion: Pinocytosis (exception) A lipid:aqueous drug partition coefficient The ionization state Spontaneous movement of solutes from high to low concentration The pH and the drug pKa (determining the drug’s ionization state) follows: Fick’s Law of Diffusion
Fick’s Law of Diffusion Passive diffusion
To describe the passive flux of molecules down a conc gradient Does not involve a carrier, is not saturable, shows low structural specificity Fick’s Law describes passive movement down concentration gradient The mechanism by which the majority of drugs gain access to the body Water-soluble drugs penetrate the cell through aqueous channels Charged drugs will be influenced by membrane potentials Lipid-soluble drugs readily move across most biological membranes α lipophilicity and membrane area Factors affecting the Passive diffusion: Since under usual conditions: 1/α membrane thickness Lipid:Aqueous drug partition coefficient The ionization state The pH and the drug pKa (determining the drug’s ionization state) ∴ Diffusion rate α drug concentration
Absorption mechanisms-facilitated transport Passive diffusion vs. Facilitated diffusion
Facilitated transport (diffusion) 1. Does Not 1. Does Not need energy, need energy, Similar to Active transport: 2. Work with 2. Work with conc. gradient conc. Gradient Carrier mediated Can be competitive 3. Carrier Can be saturable mediated 4. Saturable
Does Not need energy, work with conc. gradient
7 Absorption mechanisms-active transport Absorption mechanisms Active transport Against conc. gradient, do not stop at equilibrium, cause intracellular accumulation Active transport vs Diffusion
Examples : Na, K Amino acids may be saturable Vitamins Against conc. gradient Depending on Sugars transporting carrier or Needs energy (ATP) Hormones enzyme Can be competitive Larger drugs May be saturable
Absorption mechanisms-convective transport Absorption mechanisms
Pinocytosis Convective transport Ion-pair transport Absorption thru (Endocytosis) pores (7-10 A), for MW up to 400 Fatty acids Diffusion controlled, Vit. A,D,E,K Driven by Parasite eggs conc. gradient Vit B12 complex
Both ions and Not so important neutral molecules can pass, for drugs To form uncharged complex Particles or droplets engulfed Depending on size (∵size restriction) to pass membrane Not important for drug absorption
Summary –factors affecting drug movement
A. Charge (= polarity = affected by environmental pH) B. Lipophilicity (fat loving) C. Concentration gradient D. Molecular size E. Temperature of cellular environment Lecture 2 F. Thickness of membrane
Small, lipophilic drug with high concentration gradient, moves the best
8 Drug administered in solid form must completely A= Drug absorption dissolve before they can be absorbed
Absorption: Uptake of a drug into the systemic circulatio = from site of administration to systemic circulation (blood stream) Lipid membrane Break into smaller pieces
move across
Drugs in liquid dose form do not have a dissolution step From solid to solution thus are more readily absorbed Villi than solid dosage form
How well drug absorbed is expressed by Factors affecting bioavailability Bioavailability (F) Dissolution of drug F is the percentage of the administered drug Drug form or formulation (salt, easter etc.) which reaches the systemic circulation Dosage form (tablet, capsule) Amt of drug in Plasma Route of administration F = GI tract Dose pH (ionization of drug) AUC oral = metabolism (first pass effect) AUC i.v. bacteria stay time (emptying time)
(Ranges from 0 –1) food content
Dissolution of drugs on absorption Effect of drug formulations
Taking medicine with more water Pro-drugs = increases drug absorption drugs that need to be metabolized before desired action is available
Dexamethasone: can be prepared in two derivatives
The rate of absorption may be the same but the extent of absorption may be different hydrolyze slower than =For longer duration = For faster availability
9 Effect of drug formulations Effect of dosage forms
Serum concentration of dipyridamole (anti-coagulant) in 5 experimental subjects
Whole tablet of dipyridamole Lower peak conc. and variable rate of absorption
Crushed tablet of dipyridamole
Higher peak conc. and faster absorption
SulfobenzoatePhosphate hydrolyzedhydrolyzed faster slower and better so longer so higher duration plasma is expected conc. is reached
Effect of administration route Lipophilicity vs. hydrophilicity
Hydrophilic drugs: better absorbed through IM, SC (∵administered in intercellular space)
Lipophilic drugs better absorbed through intestine (∵tight cellular junctions)
Applications: Sustained release:
IV > SL >IM ≧ SC ≧ PO ≧TP Intestinal therapy: Instant-sec--min------hr----hr
Regular vs. Sustained Release Think about it!
IV bolus vs. IV infusion in digoxin
Positive inotropic agent by inhibiting Na-K-ATP pump thus providing more Ca available for cardiac muscle contraction Low Therapeutic Index Side effects including anorexia, vomiting, diarrhea, and arrhythmias
=lower steady state conc & longer duration IV bolus or IV infusion?? Why? Lower overall bioavailbility
10 Effect of pH and ionization Effect of pH and ionization
Many drugs are acids or bases Many drugs are acids or bases
BH+ BH+
B B
Only the non-ionized form can cross the membrane by passive diffusion Only the non-ionized form can cross the membrane by passive diffusion
Effect of pH on Ionization Commonly used pKa values
pKa pKa
pKa
Henderson and Hasselbalch Equation Henderson and Hasselbalch Equation
Describes relationship between pH and pKa for:
Bronsted-Lowry acid, a H+ donor Charged Acids Bases
Bronsted-Lowry base, a H+ acceptor
Uncharged
11 Ion trapping of acidic drugs Ion trapping of acidic drugs
By definition: - (0.6-8)=7.4
Henderson and Hasselbalch Equation:
Ex.
~90 % Phenobarbitals is “trapped”in this urine
Ion trapping of basic drugs General rule
See examples below
Ex. Acidic drug is more ionized in alkaline environment
Basic drug is more ionized in acidic environment Quinine~90 % Quinine that can is cross“trapped the membrane”in the plasma is 1/10 of that can not
Ion trapping of salicylate Basic drug is better absorbed in alkaline environment
See examples below
12 Ionization of Quinine in different pHs Ion trapping of Aspirin in the stomach
1. Acidic drug in acidic Environment, thus non-ionized and readily across the lumen
2. Once in the cell, intracellular environment becomes alkaline, thus ionize the drug and “trap”the drug within the cell
Is Ion trapping all bad? Major facts for drug absorption
Situation 1: Drug overdose Situation 2: Drug has toxic metabolites eliminated by kidney The most important absorption mechanism Passive diffusion Active transport Alkaline urine Acidic urine
GI tract is the most important absorption site Small intestine Stomach Large intestine
Factors affecting GI absorption Presystemic metabolism
Drugs metabolized before entering the Factors affecting GI absorption systemic circulation metabolism in gut wall Surface area terbutaline, salbutamol 1st pass effect Food interaction First pass effect Degradation by GI enzyme or gastric acid Gastric emptying time (slow emptying delay resorption) After GI absorption, drugs enter liver (through portal vein) pH for metabolism before they could reach the site of action, therefore, the bio-availability of drugs is greatly reduced
13 First pass effect Degradation by enzyme and other factors
40 mg oral dose of the drug gives rise to the same target organ concentration as delivered by 2 mg injection of the drug
The first-pass effect of tranquilizer Diazepam is so extensive that little reach the blood, DO NOT recommend PO
Effects of food on drug absorption Example of food delaying absorption
Whole tablet of dipyridamole
Crushed tablet of dipyridamole
Whole tablet 2 hr before lunch Legend: Slowed absorption with food & Reduced = drugs whose absorption are Un-disintegrate tablet give 2nd peak reduced by food intake
Effects of food content on drug absorption Effect of tissue perfusion on absorption Griseofulvin
Clinical Application --why is Ep co-administered
Lidocaine: Epinephrine: local anesthetics α1 adrenergic agonist induce local numb Vasoconstrictor ↑ blood pressure
14 D= Drug distribution
Most drugs are not beneficial unless they reach the target tissue
Imagine a cardiac drug can not reach the myocardium? Lecture 3 Imagine a tranquilizer unable to reach the brain?
Definition Movement of drug from the systemic circulation into tissue Reversible movement of drug between body compartments
D= Drug distribution Drug distribution
Movement between central and peripheral compartments For a 70 kg human ~ 60% Body Weight
~ 20% BW 45L ~ 40% BW
15L 30L ~ 5% BW ~ 15% BW
5L Higher 10L blood perfusion rate Lower
Drug distribution pathway Barriers to Drug Distribution
Both hydrophilic and lipophilic free drugs can pass through fenestrations (windows, pores) in the capillary well
Drugs bound to protein
15 Blood-Brain barrier has tight endothelial junctions Drug distribution depends on how well (astrocyte, glial cells) tissue is perfused with blood
Only extremely lipophilic drugs can pass through BBB
Special barriers: Prostate: only selective antibiotics work Eye ball: need direct injection Placenta: a poor barrier to drugs
Drug distribution depends on the extent Distribution and Redistribution of drug-protein binding
•Thiopental = inductive anesthetic •Very lipophilic=quickly pass BBB and distribution to the brain
1. Thiopental produces anesthesia within seconds after IV , why? Only protein-free drug: Distribution: drugs quickly distribute to highly perfused brain can pass membrane is pharmacologically active 2. Animal begins to recover within minutes after anesthesia, why? can be metabolized Drug elimination? is excreted Distribution: drugs continue to distribute to other tissues, dropping blood concentration in the brain Redistribution=drugs distribute to the brain (tissue), back to the blood, and then to a second tissue (ex. fat)
Drug-protein binding may be decreased Representative proteins to which drugs by liver and protein-losing bind in plasma renal diseases
α-Acid glycoprotein
RBC is another major resource Mostly for acidic drugs binding Mostly for basic drugs binding
16 Calculation of drug-protein binding (Fb) Protein binding data of some drugs
Fu=fraction unbound Equilibrium constant Ka D P DP Low [DP] protein Ka = ∴[DP]=Ka x [D] [P] binding [D] [P] [D] [DP] Fu= Fb= = 1- Fu [D]total [D] total high protein binding Can be experimentally measured w/o knowing protein Drug-protein binding information can be very important for concentration [D] total =Dosage if given IV Ex. microdialysis drugs with high protein binding (see below)
drug-protein binding is a competitive process, Replacement of high protein bound drugs depending on (1)affinity (2)concentration can increase toxicity
10 As bound to protein A B has higher affinity for protein B A A ↑hemorrhage B 10% change A A B A A [A] doubles Hypoglycemic coma A B could displace A and ↑ [free A] For a drug that is 99% protein-bound, 2% change in protein binding Use of aspirin, phenylbutazone, sulfa drugs, etc Can cause plasma drug concentration “Triples” may potentiate the anticoagulant effect of warfarin and high protein-bound drugs require loading dose maintenance dose hypoglycemic effect of tobutamide
How well drug distributed is expressed by Summary for drug-protein bindings Volume of distribution (Vd)
1. Occur in plasma & tissue 2. Primarily to albumin 3. Is reversible 4. By weak bonds (van der waal’s and ionic bonds) 5. Mostly unspecific to many drugs 6. Can have more than 1 binding sites 7. Can be displaced by drugs w/ higher affinity 8. Delays urinary excretion (∵not filtered) Dose 9. Increases biological half-life (∵not filtered or metabolized) Vd = Ranges from 7 –40000 L Possible? [Plasma drug] 10.Can be saturated What does Vd > 5L in a 70 kg man mean?
17 Volume of Distribution (Vd)
Assumptions: 1. Drug is equally distributed throughout the body 2. Blood concentration is equilibrium to tissue concentration
Apparent Volume of Distribution (Vd) Lecture 4 is more accurately used because Vd is a mathematically derived value, not a real volume
Vd can be misleading: Ex. Digoxin is sequestered in the muscle and heart
Vd can be different in different body composition: Ex. a fat dog and lean dog with the same weight
M=Drug biotransformation Introduction to Drug Metabolism Biotransformation: Metabolism Definition: conversion of a drug into metabolites Purpose: to increase hydrophilicity of the drug A drug’s Fate in the body But I thought that metabolism is: Is classified as phase 1 and phase 2 pathways: ConversionBiotransformation of the drug into another phase 1: non-synthetic or functionalization reactions chemical form (metabolites) ? introduce or uncover a hydrophilic functional group phase 2: synthetic or conjugation reactions is part of the metabolism process addition of an endogenous, water-soluble small molecules
M=Drug biotransformation Major phase I & II reactions
Common drug biotransformation processes: Include two major reaction phases:
Phase I Phase II What does it do?
Introduce/expose Add functional group functional group
The purpose? To ↑drug polarity for better excretion Glutathione conjugation Phase I & II does NOT always occur together Fatty acid conjugation Phase I does NOT always precede phase II reactions cholesterol conjugation Glucoronide conjugation = addition of glucoronide
18 Introduction to metabolizing enzymes Relationships of phase I & II reactions Cytochrome P-450
P-450 plays a central role in the metabolism of many xenobiotics, catalyzing both detoxification and bioactivation reactions
P-450 can introduce hydroxyl groups (-OH) into structures as un-reactive as hydrocarbon chains and aromatic rings, initiating conjugation process
Acetaminophen and chloramphenicl go through both Phase I & II metabolisms Location of enzymes: But with different pathways Liver >> intestine ~ lung ~ skin Other drugs above undergo either phase 1 or phase 2 metabolisms
Cyp 450 dependent-mixed-function oxidases (MFO) Biotransformation and activity Monoxygenase responsible for oxidation and reduction of drugs
Electron transfer system Heme protein containing iron
Oxygen
Overall reaction: + + RH + O2 + NADPH + H ROH + H2O + NADP Drugs could gain or lose their pharmacological activity after metabolism
Some commonly seen Side-chain hydroxylation of drugs that have active metabolites Pentobarbital
s- n n o Pentobarbital Hydroxypentobarbital a ti tr a o m n Aliphatic hydroxylation i r io Some commonly seen B o t f va drugs are ti actually c active metabolites a
Active drug Inactive metabolite
19 Deamination of Amphetamine Demethylation of Codeine
Codeine Morphine Amphetamine Phenylacetone Oxidative deamination O-dealkylation
Active drug Inactive metabolite
Active drug Active metabolite
Phase II conjugation reactions Mechanisms of conjugation Phase II conjugation reactions 2.1. Use To raiseof an the appropriate energy leveltransferase for preparationto complete of conjugation the connection reaction
The most common conjugating agents are:
The most seen functional groups for conjugation are: -OH, -COOH, -NH2, -SH =benzoic acid-glycine conjugate
Biotransformation reaction by Biotransformation reaction by functional groups functional groups
When you see the (left side) functional groups on a drug, it is likely Examples refer to salicylic acid biotransformation in the next page to perform the (right side) conjugation reaction and sequences
20 Biotransformation of salicylic acid Conjugations are not all good
Sulfanilamide Glycine Glucoronide conjugation conjugation Acetylation: Hydroxylation OH-Glucoronide Hydroxylation conjugation
Glycine conjugation Acetylation of sulfanilamide, sulfadiazin and sulfisoxazole form less water soluble metabolites
These metabolites may precipitate in renal tubules, SA=sa causing kidney damage and crystaluria
Regulation of drug biotransformation Regulation of drug biotransformation Age Many factors affect the pathway, as well as the extent of biotransformation
Metabolic capacity is reduced in old and newborn Ie. Ability for sulfation is developed at birth
Ex. Gray syndrome: Newborn (<2 mo) can not perform glucoronidation to chloramphenicol, use of such drug causes cardiovascular collapse
Regulation of drug biotransformation Genetic polymorphism Metabolism of mephenytoin enantiomers
Isoniazid Both R and S are But the metabolism of metabolized by S form showed hydroxylation AcetylationMajor metaboliccan be pathway fast or slow is Acetylation genetic polymorphism
Isoniazids are metabolizing fast and show low plasma conc Eskimose and Japanese are FAST acetylators Usually S is metabolized faster Caucasians are ∴[S]<<[R] SLOW acetylators t1/2 = 2hr (s) vs 76 hr (R) Some are Slow metabolizer ∴has increased [S]
21 Drug--Enzyme Interactions Regulation of drug biotransformation Enzyme inhibition 1. Enzyme competition 2 drugs using the same enzyme Sinemet=Carbidopa+ Levodopa 1:10 or 1:4
Carbidopa inhibits Blood Brain 2. Enzyme inhibition 1 drug ↓ the metabolism of Dopamine the other drug decarboxylation, thus ↑ Dopa efficiency to cross 3. Enzyme induction drug ↑ the metabolism of drug BBB, thus ↑ dopamine conversion in brain 1. auto induction drug↑self metabolism Dopamine does NOT cross BBB If too much Dopamine is 2. foreign induction drug ↑ other drug’s metabolism formed in the blood, less will cross BBB to treat Parkinson’s Enzymes may ↑when they are repeatedly exposed to the drug Pro-drug Levodopa (Dopa) can
Shortening the drug’s effective time Dopa is decarboxylated to Dopa Develop TOLERANCE (ex. Barbiturate, narcotics, alcohol) become Dopamine
Competition of enzymes Drugs inhibiting metabolism of other drugs Inhibitors To be Inhibited Inhibitors To be Inhibited
Anti uric acid synthesis Anti purine synthesis =anti-inflammatory =anti-cancer
Aldehyde dehydrogenase inhibitor ↑aldehide accumulation
Quick absorption, slow excretion Phenytoin, warfarin Ideal for treating alcoholism Hypoglycemic agent
u opioid analgesic, 1/7 of morphine potency =Demerol
Regulation of drug biotransformation Regulation of drug biotransformation Enzyme induction foreign inductions
metabolism
Metabolism
Foreign induction Auto induction Metabolism
Stimulation of metabolism of itself
22 Example: Induction of cytochrome P-450 Example: Induction of (phenacetin) metabolism
Phenacetin is readily de-alkylated to acetaminophen =insecticide, charcoal
CYP 1A1 & 1A2 Commonly used
People who took phenacetin and charcoal beef have significantly lower plasma phenacetin, this is a typical example of CYP 1A1 & 1A2 induction Other common dietary factors which are also P-450 inducers include cigarette (1A, 3A), coffee (1A, 2E) and alcohol (2E),-wonder why you are tolerant to caffeine or alcohol? SOME vegetables like cabbage, cauliflowers and asparagus are p-450 inactivators (1A, 2E)- wonder why they are anti-cancerous? So drugs gradually lose their effectiveness
Inhibition of Cytochrome P-450 Example: Enzyme inhibition Naringenin and Bergamottin Exposure to certain xenobiotics decreased P-450 ability to metabolism Inhibition could result in higher plasma conc and toxicity • Grapefruit can have a number of interactions with drugs, often Drug-drug interaction complicated this situation where one drug can increasing the effective potency of compounds. Grapefruit contains ↓ the metabolism of other co-administered drugs naringenin and bergamottin, which inhibit the cytochrome P450 4 mechanisms are proposed for P-450 inhibition isoform CYP3A4 in the liver. It is via inhibition of this enzyme that Competitive inhibition 1) two drugs (substrates) compete for the same P-450 grapefruit increases the effects of simvastatin, terfenadine, 2) non-substrate xenobiotics bind P-450’s active site thus block felodipine, nifedipine, verapamil, estradiol, midazolam, and the real drug binding and metabolism cyclosporine A. Non-competitive inhibition Grapefruit seed extract is a strong antimicrobial with proven activity 3) production of metabolites with higher affinity to P-450 against bacteria and fungi. It also has antioxidant properties and low than parent drug, thus ↓ parent drug metabolism glycemic index 4) production of highly reactive metabolites that bind to P-450 and destroys P-450 (suicide substrate) Away with grape fruit products while taking medicines
Summary Cats are not Little Dogs Regulation of drug biotransformation Species differences in biotransformation: 1. Genetic polymorphism A drug that’s safe in one species may produce severe Unwanted drug toxicity 2. Enzyme inhibition side effects in another 3. Enzyme auto induction Less glucoronic acid conjugation in cats 4. Enzyme foreign induction Aspirin Treatment Failure 5. Enzyme competition Acetaminophen 6. Stereo-specific metabolism Liver failure, hemolysis, heinz body, methemoglobin
http://www.petplace.com/cats/acetaminophen-toxicity-in-cats/page1.aspx
23 Detoxification of acetaminophen Detoxification pathways of acetaminophen
2 1
1=major pathway 3=intoxication pathway 4=detoxification pathway 3
(N-acetyl-papr-benzoquinone imine) Malnutrition and alcohol 4
(barbituate) ↑susceptibility to Supplement of N-acetylcysteine Tylenol toxicities keep this pathway going
E = Drug excretion movement of drug out of the body Drug excretion pathways
Pulmonary Sweat Renal Hepatic Hair Lecture 5 exhale Salivary Nail Milk Hooves
Glomerular Tubular Biliary Tubular filtration reabsorption secretion 125 ml/min 500 ml/min (inulin) Intestinal 625 ml/min ex. P-aminohippurate, penicillin
Drug excretion- Renal Nephron Drug excretion-Renal
Mechanism for renal excretion: Renal
Tubular Tubular secretion reabsorption Glomerular filtration Active transport systems Active or passive Carrier mediated pH-dependent process For MW<500, Capacity limited (saturable) Most drugs has small MW water soluble conjugates
24 Renal regulations of low MW molecules 1. Most molecules are Factors affect renal excretion of Drug resorbed by conc gradient Proximal 2. Angiotensin II Glomerular Henle’s loop Distal tubule stimulate resorption of tubule Collecting duct Na, Cl &H2O Renal pelvis ureter 3. Na-K-2Cl co-transporter. Renal perfusion↓ Active secretion Reabsorption occurs here, ADH stimulate it Hypotension of penicillins Dehydration Furosemide blocks it cause high lipophilic drugs resorbed Very little is Blood loss urinary penicillin Shock while hydrophilic drugs resorbed from 4. Na-Cl co-transporter concentrations ↑sympathetic stay in urine here & down Thiazides block it This is where acidifying Drugs 5. Aldosterone↑Na resorp ↓ drug elimination or alkalinizing the urine hereafter are by open Na channel, to modify the ionization considered sti Na-Cl co-transporter ↑renal perfusion status of the drug works eliminated ADH H2O resorp IV fluid infusion =↑ drug elimination
Drug excretion-Renal Drug excretion-Renal
Tubular re-absorption: passive or active transport (glucose) Tubular secretion: by 2 active transport carrier systems:
More amphetamine excreted in H2O re-absorption=1.5L/day 1. Acid system: ex. Reabsorption is pH dependent: penicillin, more ionized = less absorption probenecid
2. Base system: ex. Less amphetamine excreted ranitidine in alkaline urine (∵less ionized, more re-absorption) So amphetamine is more likely an acid or base? pKa=9.8
Drugs possibly through Drug excretion-enterohepatic Enteohepatic & biliary excretion Liver-bile-intestine pathways
For molecules with strong polar groups Such as Conjugates
Mostly for larger molecules (MW>500) Enterohepatic circulation Drug can be secreted into the bile Primary to the intestine and hydrolyzed in the intestine secondary re-absorbed to liver for systemic availbility bile salts
A reverse of conjugation elimination procedure
25 Extraction Ratio (ER) Drugs by hepatic high Represents the magnitude of the first pass hepatic excretion extraction ratio effect >0.5 A drug with a high ER exhibits high extraction by the liver. Flow limited: excretion of High ER drugs may show higher variations in inter- low high extraction drug is patient bioavailability than low ER drugs. extraction ratio limited by blood flow <0.3 High ER = fast metabolized by the liver Capacity limited: C in- C out excretion of Extraction ratio= low extraction drug is C in limited by enzyme capacity
Other excretion pathways
pH 6.4-7.6 Most drug in blood will be detectable in Milk Passive diffusion ex. Sulfonamides Theophylline
Skin Pulmonary Salivary
Volatile substances A minor pathway pH=6.5 (5.5-8.4) Ethanol-breath Passive diffusion for lipid soluble, non-ionized Paraldehyde-hypnotic Vitamin B Salivary = free plasma level anesthetics prednisolone glucocorticoids
How fast drug excreted can be expressed Clearance (CL) by clearance Refers to a drug’s rate of elimination by all routes, normalized to the concentration (C) of the drug in biological fluid (such as Unit=volume/time= ex. L/day blood or plasma): CL = rate of elimination / C CL = Vd x Kel CL = Vd x (0.693 / t 1/2) Units on clearance are volume per unit time (ex. L/hr) Systemic clearance is additive, and is a function of elimination by all participating organs: Thus total drug removed α [plasma drug] and Clearance CL systemic = CL renal + CL hepatic + CL other organs
26 Clearance - Renal Clearance - Hepatic
Renal clearance determines the rate of elimination of Hepatic clearance contributes to the rate of elimination unchanged drug and metabolites following metabolic transformation of the parent drug to metabolites. Dependent upon: Since this type of elimination is usually not “saturable,”the properties of the drug itself rate of elimination by the liver is typically 1st order and water solubility, ionization state, protein binding directly proportional to drug concentration. physiological parameters of the kidney Factors affect hepatic clearance include: pH, rate of filtration, rate of secretion, blood flow, & number of induction of hepatic enzymes (by other drugs or by self) functional nephrons presence of hepatic disease, patient age, and genetic polymorphisms in hepatic enzymes
Factors affect drug clearance Drug elimination
∵Proportional to liver or kidney size Need adj by STD= 70 kg or 1.73 m2 ↓protein binding=↑[free drug]=↑Cl
High extraction drug has reduced [free plasma drug]
Needless to say
Will affect blood flow to kidney and liver Kd is also referred as Kel The elimination process can be expressed by two mathematical expressions
Drug Elimination: 1st Order (non-saturating) Kinetics 1st order and zero-order kinetics Most drugs exhibit 1st order kinetics The kinetic order refers to the exponent of the drug A constant fraction of drug is eliminated per unit time concentration (usually, n = 0 or 1) in this equation The fraction of the dose eliminated in a given time is independent of the dose △[drug] The amount of drug elimination is equal to the plasma drug = [drug]nK concentration multiplied by the drug clearance (Cl x [Drug]) △time The t ½ and clearance of the drug remain constant as long as renal and hepatic function do not change (it is independent of amount of drug presented)
27 First order elimination Zero-Order Kinetics
The fraction of the drug that is removed at any time remain constant It is dependent on plasma concentration A few drugs (such as ethanol) exhibit zero-order kinetics =initial conc the rate of drug elimination is constant and is Log transformation independent of the plasma drug concentration A straight line [Plasma] reduction by ½ did not reduce the clearance is inversely proportional to the drug conc. elimination time by half Saturating kinetics: Example here: In some cases, drugs exhibit zero-order elimination at For every hour, high doses; the reason that the rate of drug elimination [Drug] reduced by half ie. t ½ =1 hr becomes constant is that the elimination process becomes saturated. t1/2 = Time for the drug concentration to reduce by half
Zero order elimination Concentration-Dependent Kinetics
The same Amount of the drug is disappeared at a given amount of time regardless how much drug is presented 1st Order Kinetic at low drug concentration region Examples include alcohol Zero-Order Kinetic at high concentration region phenytoin salicylate metabolism It is enzyme saturable 5 dC / dt = - k [Plasma] reduction by ½ The rate of decrease also reduce elimination time is independent by half of concentration, depend only on k 3.3 6.6
1st order vs. Zero-order Kinetics Half-life (t 1/2)
1st order Kinetics •The time required for a drug to drop to half of its original Drug conc will conc plateau •Reflect how efficiently the clearance organs are functioning •Dictate how frequently the drug must be given –2 hr in most antibiotics vs. 2 d in Phenobarbital •t ½ of a drug mainly excrete by liver would not change Zero-order Kinetics significantly by kidney disease, and vice versa (hepatic Drug conc elimination process is not directly affected by renal function) will keep increase When choose drugs for animals with renal or liver dysfunction, knowledge of major elimination route become very important in choosing the drug
28 Half-life (t 1/2) Half-life (t 1/2)
•The elimination half life (t ½ ) for a given drug is calculated using the drug’s elimination rate constant Kel: t ½ = 0.693 / Kel
•The half-life of a drug can be affected by: – disease states : which can affect Vd and Cl –patient age: which can affect Vd
Drug elimination (t ½) Think about it!! Fit the curves
1. Plasma for 2 2. Major organs: kidney, e s
rearrange liver, o D
heart, f o
brain t n
3. Lean: e c r
muscle e skin P 4. Fat t ½ is the time it takes for C to drop to half of its value
Relationship between t ½ and Kel Accumulation Factor
A. With repeating drug doses, a drug will accumulate in the body until dosing ceases. B. Practically, accumulation will be observed if the dosing interval is less than 4 half-lives. 0.693 C. Accumulation of the drug is inversely proportional to the t 1/2 = fraction of the dose lost in each dosing interval: Kel 1 +Kel 2+…. Accumulation factor = 1 / Fraction of drug lost in one dosing interval 0.693 = = 1 / (1 –Fraction of drug remaining) Kel renal +Kel hepatic+…
29 Steady state concentration (Css) Derive the Css Formula
Css occurs during: To maintain a steady-state, the drug eliminated should be 1. constant infusion when the infusion rate = the rate of replenished by the maintenance dose, elimination. either by constant infusion or repeated doses 2. Repeated dosing until all plateau and trough conc become the When using infusion: Maintenance dose = Cl x Css same. When using repeated doses: The steady-state drug plasma concentration can be calculated using Dose = D x F = Cl x Css x Tm the following formula: = Kel x Vd x Css x Tm Css = (F x D) / (Kel x Vd) x Tm (see next slide for how is it derived) Rearrange for Css, Css = (D x F) / (Kel x Vd) x Tm D = dose of drug administered Tm = dosing interval (in hours)
Determination of IV infusion rate Relation of t ½ to Css (Plateau principle)
For constant infusion and 1st order elimination (assumption), Goal: achieve a desired steady-state level. How quick a drug reaches steady state is determined by the Rate of infusion must equal rate of elimination drug’s elimination rate (Kel) and can be expressed by t ½ Rate of infusion = (Kel x Vd) x Css mg/hr 1/hr x L x mg/L One t 1/2 = 50% Css = Cl x Css Two t 1/2 = 75% Css (50%+25%) L/hr x mg/L Three t 1/2 = 87.5% Css (50%+25%+12.5%) Four t 1/2 = 97% Css (50%+25%+12.5%+6.25%) Maintenance infusion rate = General Rule: Time required for a drug to reach steady state=Five t ½ Loading dose = When administered at maintenance rate, a drug that is eliminated slowly reaches steady state slowly or quickly?
Relation of t ½ to Css (Plateau principle) Relation of t ½ to Css (Plateau principle)
After the infusion begins or stopped at a specific time point, Repeated dosing regimen until all plateau and trough conc it will take 3-5 t ½ from that point are the same, which is usually taking 3-5 half-lives to reach steady state
30 Think about it?
Can a higher maintenance dose (without a loading dose) resulted in quicker time to reach steady state?
Ie, can 100 mg bid reach steady state quicker than 50 mg bid?
NO, NO, NO, NO, NO Lecture 5 - 1 Higher dose only resulted in higher blood conc and more drug elimination, it still required 5 t ½ to reach steady state i.e. time to reach steady state will be THE SAME, but Higher dose will have higher peak and trough
Example question #1 Answer to example question #1
Use semi-log paper to draw conc.-time plot
Use semi-log paper to draw conc.-time plot
Example question #2 3.34 Metoclopramide was given to a patient in a 5 mg IV bolus dose. Plasma conc were determined to help establish an optimal dose regimen. Time after dose (hr) Plasma conc. (ng/ml) 4 30 8 15 12 7.5 16 3.75 1. What is the order of the decay? 2. Estimate the initial conc of the drug? 3. What is the half-life of the decay? 4. What is the rate constant of the decay? 5. What is the Vd of this patient? 6. How long will it take to eliminate 87.5% of the dose?
31 Example question #3 Example question #4 Lidocaine infusion. A patient (70kg) is to take 2 doses per day of Css=2 mg/L, t ½=80 min, Vd=0.7L/kg sulfamethoxazole (t1/2=10 hr) to maintain a Css of 3μg/ml Find 1. infusion rate, 2. loading dose in a Vd of 0.2 L/kg. What is the maintenance dose? Solution: 1. Infusion rate = Maintenance dose =
Cl = Kel x Vd =
2. Loading dose=
Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions
1. Amikacin is eliminated by the kidney with a Clearance of 1 2. The half-life of carbenicillin in its Vd (0.2 L/kg) is 1 hr. If a ml/min*kg, from a Vd equivalent to the ECF (0.2 L/kg). constant IV infusion of 700 mg/hr is begun, What is the plasma half-life for a 50 kg person? approximately how long will it take for the plasma conc to reach a steady state level of 100 mg/L in a 50 kg adult? A. 12 sec B. 1 min C. 50 min D. 2.5 hrs E. 15 hrs A. 4 hrs B. 8 hrs C. 12.3 hr D. 20 hrs E. 24 hrs
Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions
3-1. What is the IV loading dose required to raise the 3-2. In the previous problem, what is the maintenance infusion theophylline plasma level from 5 mg/L to 15 mg/L in a rate required to achieve a steady state plasma theophylline 50 kg adult? The Vd of theophylline is 0.5 L/kg level of 15 mg/L in the 50 kg adult? The Cl is 0.04 L/hr*kg
A. 5 mg B. 50 mg C. 250 mg D. 500 mg E. 2.5 mg A. 0.6 mg/hr B. 2 mg/hr C. 30 mg/hr D. 300 mg/hr E. 750 mg/hr
32 Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions
3-3. In the previous problem, what is the required dosing 4. For a zero-order elimination, the time it takes for the plasma interval for oral administration of a 250 mg tablet assuming level of a drug to fall below the therapeutic level is: rapid and complete absorption? A. The half-life for elimination A. 0.8 hr B. 4.8 hr C. 8 hr D. 12.5 hr E. 25 hr B. Directly proportional to the logrithm of the initial plasma concentration C. Dependent upon the Machaelis constant of the metabolizing enzyme D. Directly proportional to the initial plasma concentration E. Directly proportional to the reciprocal of the initial plasma concentration
Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions 6. It is desired to maintain a plasma conc of 150 μg/ml of carbenicillin in a 70 kg person with normal renel and hepatic 5. A patient has a plasma level of 24 mg/L of a drug with a first functions. Calculate the necessary IV infusion rate. The t ½ order elimination rate constant of 0.2 per hr. How long will is 1 hr and Vd is 0.18 L/kg. it take to for the plasma level to decrease to 3 mg/L assuming no more drug is given? A. 1 hr B. 2 hr C. 5 hr D. 8 hr E. 11 hr
Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions 7. The following plasma cocn (mg/100ml) of a toxic substance 8. A singledose of 400 mg of the sulfamethoxazole was administered were obtained at various times (hr) after admission to the IV to a 70 kg adult. At various times the following plasma hospital: conc were observed: Time after dose (hr) Plasma conc. (ng/ml) Time after dose (hr) Plasma conc. (ng/ml) 16.6 20 2 6 = 4 + 2 4=2.8 + 1.4 5 5 6 12.6 14 8 4 2.9 10 5 4 12 9.7 15 10 4 2.8 5 3 16 6.9 20 7 4 2.9 20 4.0 A. Calculate the initial plasma conc 4 1.2 2.8 24 B. Find the rate constant for elimination of sulfamethoxazole What is the order of the elimination? Assuming that this poison has a Vd of C. What is the clearance of sulfamethoxazole in this person 41 L, what was the rate of appearance of the substance from the whole body in the time period: 1) 0-5 hr; 2) 5-10 hr ? (Draw a Plot)
33 Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions 9. A drug is eliminated from the plasma by the following 1st order 10. A patient (70 kg) with meningitis was given a continuous pathways at the rate constant given: IV infusion of benzylpenicillin. The plasma t1/2 is 30
Excretion through the bile, Kbile = 0.6 / hr min and the Vd is 0.2 L/kg: Metabolism, Kmet = 0.25 / hr A. What is the rate of infusion required to maintain the plasma Excretion by the kidney, Krenal = 0.05 / hr conc at 20 ug/ml? A. What is the plasma half-life of the drug? B. How long will it take to reach 87.5% of the steady state level at the rate of infusion starting from 0? B. What is the plasma half-life if the metabolism of the drug is completely blocked? C. What is a suitable loading dose to allow a rapid plasma conc of 20 ug/ml? C. What is the ratio of the drug found in feces to that found in urine?
Pharmacokinetic Practice Questions Pharmacokinetic Practice Questions 11. Digitoxin is eliminated very slowly from the body; the t ½ is 11. Digitoxin is eliminated very slowly from the body; the t ½ is about 7 days in adult. The Vd is 0.5 L/kg and the therapeutic about 7 days in adult. The Vd is 0.5 L/kg and the therapeutic effective plasma conc is about 20 ng/ml. effective plasma conc is about 20 ng/ml.
11-1. Calculate the loading dose of digitoxin for a 70 kg person. 11-5. Why is recovery from toxicity slow with digitoxin?
11-6. The daily dose is very low, what’s the advantage and 11-2. Calculate the Clearance of this person? disadvantage of taking the doses every other day?
11-7. The patient calls to say he forgot the dose yesterday, Do you 11-3. Find the daily maintenance dose of digitoxin for a 70 kg person. advise double the dose to make up for yesterday?
11-4. Rely solely on daily maintenance dose, how long will it take to reach 90% of the therapeutically effective plasma conc?
了解停藥期 、標籤指示外用藥後新停藥期 之制定以及其與藥物動力學之關係
Lecture 6 Understanding Withdrawal time (WDT) and Withdrawal interval (WDI) after extra-label use of drugs (ELUD) and their relationship to pharmacokinetics
34 TVBS 一步一腳印、發現新台灣 藥物殘留對於人體危害之舉例 ~有機養殖~ 以公共衛生之觀點，長期食用藥物殘留量超過法定容許標準之畜 禽產品，對人類可能之傷害舉例包括：
96年3月4日 1. Chloramphenicol引起骨髓幹細胞障礙導致再生不良性貧血、 顆粒性白血球減少症及血小板減少症。 2. Penicillins與頭孢子素類Cephalosporins可能引起過敏性反 •我的豬不打針 應。 3. 致癌作用，如Furazolidone、 Diethylstillbestrol。 •吃牧草的雞 4. 致畸胎作用，如Pyrimethamine。 5. 不論預防或治療之用，長期或濫用抗菌劑可能會誘發抗藥性 •江醫師的魚 菌株之產生，若感染人類，可導致選擇可用的抗菌劑種類變 •中草藥及健康配方(herbal nutrient) 少。
藥物殘留(Drug Residue)之定義 藥物殘留之種類
•藥物殘留係指1. 預防或治療動物疾病，所投予動物體 1. 動物用藥品 內之動物用藥品；2. 或為了促進生長、改進飼料利用 2. 含藥飼料添加物 效率，所投予動物體內之含藥物飼料添加物；3. 或因 3. 農藥 環境汙染因素而攝入動物體內之化學物質；其以原形 4. 環境污染物質 態或代謝物聚積貯於動物之細胞、組織或器官稱之。
•Any compound present in the edible tissues of the 1. 動物用藥品： target animal that results from the use of the A. 抗菌劑類：如 Streptomycin、 Oxytetracycline、 Erythromycin等抗生素類，及 Enrofloxain與 sponsored compound, including the sponsored Sulfamethoxazole等人工合成抗菌劑類。 compound itself, its metabolites, and any B. 抗寄生蟲類：Dichlorvos、Ivermectin等。 substances formed in or on food as the result of C. 其他藥劑類：如 Dexamethasone、 Estradiol the use of the sponsored compound benzoate、 Neostigmine methylsulfate等。
藥物殘留之種類 動物用藥品在畜產品中的殘留容許量
2. 含藥飼料添加物 最大殘留量 (Maximal Residue Level，MRL) A. 抗菌劑類：如Carbadox、Chlortetracycline、 或 Neomycin、 Sulfamethazine等。 耐受量(Tolerance Level ，TL) B. 抗寄生蟲劑類：如 Amprolium、Monensin、 Salinomycin等。 • 指殘留於禽畜產品(肉、蛋、乳品)中之某藥物，其被允許之 C. 抗黴菌劑類：如Nystatin (已於94年7月被刪除) 最大殘留量或濃度 D. 荷爾蒙劑類：如Zeranol • 在此殘留量以下之藥物，被認為對人體健康之不良影響極 3. 農藥：如有機氯化合物Aldrin、Dieldrin、Lindane等及有機 低。 磷化合物Malathion、Parathion等。 • MRL或TL常以ppm或ppb表示。 4. 環境污染物：如放射性物質及重金屬毒物(砷、汞、銅、 鉛、鋁、鎘、鉻)等。
35 殘留量之表示方法 殘留容許量之訂定
•依據最敏感之實驗動物(通常是小白鼠或大白鼠)之亞急 百萬分之一(part per million；ppm) 性毒性試驗(90天)或慢性毒性試驗(104週以上)結果，求 若每kg豬肉中殘留1 mg之某藥物，即表示該藥物於豬 出藥物對實驗動物最大安全量(No Observed Effect 肉中之殘留量為1 ppm (1 mg/kg or 1μg/g)。 Level, NOEL)後，再除以對人體之安全係數，以求得該 藥物對人體之可被接受之每日攝取量(Acceptable Daily 十億分之一(part per billion；ppb) Intake；ADI)換算而成。 若每L生乳中殘留1μg之青黴素，即表示該牛乳中含1 •安全係數在亞急性毒性試驗數據為2000倍，在慢性毒性 ppb (1μg/L or 1ng/mL)之青黴素。 試驗數據時為100倍。即在老鼠試驗中投藥90天所獲得 的最大安全量的二千分之一或投藥兩年所獲得的最大安 全量的百分之一就是人體每天可攝食的安全量。
Human Food Safety Human Food Safety Requirements Requirements Toxicology
Basic toxicology Test •FDA guideline requires knowledge of Genetic toxicity tests –Toxicology 90-day feeding studies Two-generation reproduction Study with a teratology –Residue Chemistry component –Microbial Food safety Additional Studies Chronic bioassay for carcinogenicity One-year feeding studies Teratology in a second species Other specializing testing
Food Safety Decisions Acceptable Daily Intake (ADI)
No Observed Effect Level (NOEL) No Observed Effect Level (NOEL) Determined from toxicology test results ADI = (μg/kg/day) Safety Factor Safety Factors Type of study Safety factor Chronic 100 ADI (μg/kg/day) x 60 kg Safe concentration = Reproduction/Teratology 100~1000 (μg/g) Consumption Values 90-Day 1000 (=grams consumed/day)
36 Consumption Values for average Americans Establishing a Withdrawal Time
Edible products Gram consumed/day (g/d) •Run a residue depletion study under field use Muscle 300 Liver 100 conditions selecting sampling times on the Kidney 50 terminal elimination phase of the depletion Fat 50 curve closest to the tolerance Eggs 100 Milk 1500 mL
Establishing a Withdrawal Time
•Maximum conditions of use –Highest dose –Longest duration of treatment •20 animal design •4-5 animals per sampling (slaughter) point •4-5 equally spaced sampling times •Calculate the 99th percentile statistical tolerance limit with 95% confidence
訂定動物用藥品之停藥期 訂定動物用藥品之停藥期
• 動物用藥品之停藥期是依據零殘留量或殘留容許量訂 安全期間: 定。一般而言，具有致癌性或致畸胎性的藥品，不設 • 實驗動物致癌性試驗證實: 殘留容許量，其他停藥期則是依據達到殘留容許量所 具有致癌性者其安全期間為殘留期間之二倍 需要的時間訂定。 具有致畸胎性者為殘留期間之一倍 其他動物用藥品為殘留時間之二分之一倍 • 停藥期之訂定為藥物殘留期間加上安全期間。所謂殘 留期間為最後一次投藥後，可食組織中之藥物殘留濃 • 停藥期應按實足天數並以無條件進位計算，例如停藥 度降低至殘留容許量或無法檢測出殘留的期間。安全 期5.3天，係最後投藥之時間開始算起，須經6天才供 期間則因實驗動物毒性試驗之結果而異。 屠宰。但牛乳之停藥期則按實足小時數計算。
37 動物用藥品之正確使用方法 動物用藥品之正確使用方法
確實遵守停藥期、乳汁捨棄期及使用之劑量規定，才能 依推薦之對象動物使用藥物，不可使用於未指示之動物： 使食品中之殘留量合法。 • Thiamphenicol在國內僅核准添飼、肌注、皮注於豬(60 kg 以下)及雞(產蛋雞除外)，國外則另可使用於牛及綿羊。曾 • 禽畜屠宰時其體內的殘留量必須達殘留容許量以下。因 有動物藥品販賣業者擅自經口餵飼山羊而造成死亡，其賠 此應嚴格遵守自禽畜停止攝食飼料添加物或停止接受藥 償責任應歸屬販賣業者，而與製藥廠無關，因其標籤上並 未註記可使用於山羊。 物治療至准予屠宰的這一段停藥期。 • Carbadox使用對象僅指示用於豬，不可任意使用於雞； • 數種以上飼料添加物合併使用時其停藥應以其中最長之 carbadox在11-28 ppm飼添時具提高豬增重速率及改進飼料 停藥期為準。 利用率之效，但對雞無此功效;在50-55 ppm時主要用於控 • 乳牛或乳羊因疾病(含乳房炎)接受藥物治療時，不論投 制赤痢螺旋體引起的赤痢，但該病原體不侵襲雞。 藥途徑為何，其所使用之藥物有移行至乳房或直接灌入 • Maduramicin僅用於肉雞而不可使用於產蛋雞，因為此藥 乳房者，均應遵照乳汁捨棄期之規定將壓榨出來之乳汁 物會經由胎盤進入蛋內。。 捨棄。
動物用藥品之正確使用方法 動物用藥品之正確使用方法
熟讀注意事項並依指示實施 給藥。 依指示推薦劑量使用，否則可能導致失效或中毒 • Tiamulin不可與離子型球蟲藥(如monensin、narasin、 • Sulfaquinoxaline等為葉酸代謝拮抗劑(與葉酸的前驅體 maduramicin、semduramicin、salinomycin及lasalocid等)併 用，併用時則對禽畜之運動能力具不良之影響而導致死 PABA相拮抗)，會導致pyrimidines合成受阻，巨母紅血球 亡。【註：豬以外動物不得使用TTiamulin】 DNA無法製造，引起禽畜巨母紅血球性貧血。因此使用劑 量不宜過高，於病原微生物獲得控制後應予停藥，並於飼 • Maduramicin不可使用於產蛋雞，使用於雞以外的動物， 料中補充葉酸。 可能引起危險。與tiamulin及furazolidone*三者不可同時使 用。 • Arsanilic acid在50-100 ppm可提高增重速率及改進飼料利用 • *：行政院農業委員會92年11月公告，自93年6月1日起全 面禁止動物使用硝基夫喃類(nitrofurans)之動物藥品；包括 率、增加種雞及產蛋雞產蛋率。但飼料中含1000 ppm時即 furazolidone、furaltadone、nitrofuratoin、nitrofurazone、 會抑制禽畜生長，2000 ppm或以上時更可引發高死亡率。 nifurstyrenate sodium】
動物用藥品之正確使用方法 動物用藥品之正確使用方法
嚴格遵守給藥途徑 不任意混和兩種以上之藥物投藥
Lincospectin 有散劑與肌肉注射劑兩種不同劑型，有些 抗生素、合成抗菌劑與抗寄生蟲藥間的併用，可能在生 獸醫師為增高投藥劑量，故意購入散劑後加水予以溶 物個體外產生化學或物理學的變化，亦有可能在生物個 解，實行肌肉注射。此舉會對動物造成許多不良的影 體內產生藥理學上的相互作用，而導致無效或中毒之現 響，因散劑並未滅菌且溶解後的容易亦未經熱原試 象。例如，青黴素與氯黴素併用後產生拮抗作用，抗菌 驗，未調節pH值、等張性、緩衝性等，以致動物可能 效果減弱治療效果反而不佳。 會發燒或注射部位產生發炎腫脹、糜爛、硬結等病 變，對於已染病的動物更是加深其緊迫。
38 動物用藥品之正確使用方法 動物用藥品之正確使用方法 勿自行添加未經核准以及未經臨床證實藥效之藥物
β-agonist為交感神經興奮劑，亦具能減少體脂並促進 •非飼料添加之治療藥物，必須由獸醫師親自處方及監 動物體生長之效果，然而至目前為止大部分國家均未允 督使用。 許其為生長促進劑之用，勿自行添加。
【註：β1-作用：心機能亢進、促進脂肪分解；β2-作 In conclusion: 用：平滑肌鬆弛、促進肝醣分解。殘留的副作用如下： 避免 ELUD (Extra-Label Use of Drugs) β1-副作用：對有心血管疾患之病人如高血壓者會誘發 腦溢血；有狹心症與鬱血性心衰竭者會因心臟工作負荷 任何未依標籤指示的用藥皆可歸類為 ELUD 過度而心跳停止。β2-副作用：增高血糖而加重糖尿病 患者病情等。】。
藥品名稱 殘留容許量 動物用藥殘留標準 殘留部位 禽畜種類 學名 中文名稱 （ppm） 肌肉、脂 牛 0.1 Abamectin 阿巴汀 第一條 本標準依食品衛生管理法第十條規定訂定之。 腎 0.05 肌肉、脂、 牛、綿羊 0.1 第二條 本標準所稱殘留容許量係「指標性殘留物質 Albendazole 乳 (marker residue)」之含量，包括該藥物原體及與該 肝、腎 5 藥物殘留量具明顯關係之代謝產物。 牛、豬、綿 0.01 肌肉、肝、 羊、山 腎、脂 羊、家禽 第三條 食品中之動物用藥殘留量應符合下列規定，本表 Amoxicillin 安默西林 類 中未列之藥品品目，不得檢出。若表中藥品品目 非屬行政院農業委員會核准使用之動物用藥，僅 乳 牛、綿羊 適用進口肉品。 肌肉 魚(3) 0.05 第四條 本標準自發布日實施。 肌肉、肝、 牛、豬 0.01 腎、脂 Ampicillin 安比西林 乳 牛 肌肉 魚(3) 0.05
共約120項藥品請參考 藥物殘留標準是一個經常動態更新的資料庫 動物用藥殘留標準(農委會網頁) 由於抗生素等動物用藥濫用議題已成國際焦點，加上分析 備註 方法之不斷進步，各國對於禽畜水產食品之衛生安全標準 •註1.表中乳汁之殘留容許量單位為mg/L。 及檢測極限等之要求日趨嚴格。美國、歐盟等國對進口食 •註2.魚、蝦及大明蝦僅准予殘留Oxytetracycline，而不得殘 品中殘留之抗生素等動物用藥之把關均日漸嚴格。日本近 留Chlortetracycline及Tetracycline。 期也因此大幅修訂其動物用藥殘留標準。自從日本由泰國 •註3.本標準所列之魚及蝦種種類係指行政院農業委員會訂 定之動物用藥品管理法之水產動物用藥品使用規範指定對 進口的蝦、蟹相繼檢驗出氯黴素，大陸銷歐盟的蝦及吳郭 象水產動物。 魚被檢驗出氯黴素殘留、鰻魚中檢出有Enrofloxacin以來， •註4.Sulfadimethoxine與Sulfamonomethoxine兩者殘留量合 美國及歐盟對我國禽畜水產品的仰賴即與日俱增。因此， 計不得高於0.1 ppm。 對於各國變動中的標準，應該有機動性的了解。
39 藥物殘留標準是一個經常動態更新的資料庫 藥物殘留標準是一個經常動態更新的資料庫
世界各國經常都會依其國家的經濟情況、社會文化等因 自2006年5月開始，日本決定對所有食品中可能的農藥、動物 用醫藥品的殘留基準 (MRL) 予以正面表列。目前暫定的殘留 素，在殘留方面訂立適合自己國情的耐受藥量(Tolerance 基準中共有647種，其中農藥約400種，動物用藥及飼料添加物 Level)和殘留停藥期(Drug Withdrawal Time) 有200多種，水產品用醫藥品26種。但尚未完成所有品目檢驗 日本訂定最嚴格的「零」殘留或至少訂出「最低可能」的 方法的建立，已訂有MRL的農藥目前有229種，動物用藥30 允許殘留量，例如磺胺劑(Sulfamethazine)必須在0.05 ppm以 種。此正面表列法表預計每五年檢討修正一次。 下。 對未列安全殘留量者採用“一律基準”， 瑞典為防止抗菌劑在肉品的殘留，更全面禁止抗生素或抗 EU, Japan 0.01 ppm 菌劑在飼料中長期使用。 Canada and New Zealand 0.1 ppm USA 0.01-0.1 ppm 。
Journal of Food Protection, vol. 67, No. 3, 2004
Feasibility of using half-life multipliers (HLM) Background to estimate extended withdrawal intervals • ELUD could potentially lead to violative residues in food animals. An (WDI) following the extralabel use of drugs appropriately extended WDI is essential to food safety.
(ELUD) • Ideally, the extended WDI should be calculated on the basis of tissue in food-producing animals t½ of the drug. HOWEVER, these data are not readily available.
• The use of HLM has been proposed as a simple alternative method to R. Gehring, RE Baynes, AL Craigmill and JE Riviere estimate the effective tissue t ½ (ETH).
• Extended WDI estimated using various HLMs, were compared with the WDIs calculated using actual tissue t ½ .
Half-life multiplier (HLM) General rule for using half-life in estimating WDT
•An accurate estimate of tissue elimination t ½ is required to predict an extended WDI. 1. Ten t ½ could render > 99.95% of the drugs •If actual tissue t ½ is not available, an alternative reduced to below tolerance level (or MRL) approach is to estimate the elimination t ½ on the basis of the label WDT. 2. A common practice among vet practitioners is to •HLM= the number of half-lives contained within assume that for the majority of the drugs, 5 t ½ the WDT to reach tolerance level (97%) is required for tissue conc to be depleted to below MRL. ∴the smaller the HLM, the longer the estimated tissue t ½
40 Relationship between time required to deplete drug to Estimated tissue half-lives (ETH) for selected tolerance when the dose is doubled versus when the drugs using various half-life multipliers (HLMs) underlying tissue t ½ is doubled
WDT ETH = HLM
Target concentration and half-lives for marker Comparison of extended WDI calculated residues of selected drugs in target tissues using different safety factors and actual tissue t ½
WDT WDI1= WDT+ ATH ETH = HLM WDI2= WDT+ ETH WDI3= WDI2 + (SF x WDT)
Comparison of extended WDI calculated Comparison of extended WDI calculated using using a HLM of 5 with different safety the two different estimates of the tissue t ½ factors and using actual tissue t ½
41 Comparison of extended WDI after addition of Conclusions safety factor to HLM calculated t ½ •For drugs with short t ½ (<36 hrs), an HLM=5 is probably adequate.
•For drugs with longer t ½ (>100 hrs), an HLM=3 is more adequate.
•HLM of 3 should be considered if a more conservative estimate is required. Or, a safety factor should be added when use HLM=5
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