PHARMACOKINETIC The aim of the pharmacokinetic study?
12 Provides the knowledge to 10 TOXIC RANGE determine the dosage and the 8 6 THERAPEUTIC RANGE necessary adaptation of plasma 4
2 SUB-THERAPEUTIC Plasma Concentration Plasma concentrations in order to 0 0 1 2 3 4 5 6 7 8 9 optimize the effect of a drug: Dose
2 PHARMACOKINETIC PHARMACODYNAMIC
3 Plasma Site of Dosage Effects Concen. Action
Pharmacokinetics Pharmacodynamics
4 Introduction to Pharmacy Drug’s effect is correlated to its concentration near to the receptor, in general effect is correlated to plasma concentration
5 4 steps determine the pharmacokinetic profile
Absorption à partir du site 1. Absorption d’administration 2. Distribution Distribution Effets 3. Metabolism [ ] 4. Elimination Métabolisme
Elimination ADME steps –occur in the same time –it is not necessary to have all the steps for all the drugs 6 PHARMACOKINETICS
Relation PK / PD
Pharmacokinetic Pharmacodynamic study
Correlation between [C] = f (t) Effect according to C [C] these processes and effect their effects on drug [C] concentrations ( C ) at Time pharmacologically relevant sites. PK/PD
Effetc/time effect
Time
Introduction to Pharmacy 7 Drug Absorption and Distribution
General route of administration: Drug must pass through the blood to reach its target
Local application for local effect 8 The fate of the drug in human body
9 Pharmaceutical forms according to the route of administration
1. Oral administration (per os):
Tablet, capsules…
Liquid forms: syrup, oral solution
10 Pharmaceutical Forms
11 Excipients
12 Excipient properties/role To facilitate the manufacture of the dosage form: diluent, binder, lubricant in a tablet, emulsifier, ... capsule shell Facilitate the use of medicines (disintegrant for tablets, solvents, flavors, sweeteners, colors ...) Adapt the pharmacokinetic profile of the active ingredient (accelerated release: effervescent form, delayed release: enteric- coated form, slow release: LP form) Ensure the conservation of the drug (antiseptic, antifungal, antioxidant, chelating buffer substance ...)
13 Composition of a drug: Gardenal
Principe Actif (D.C.I.) ex : phénobarbital + Excipient(s) (amidon, dextrine, stéarate Mg, carbonate Ca)
Conditionnement Primaire (blister, tube … )
Conditionnement Secondaire (Boîte + R.C.P.) Criteria to choose excipients: Safety Inertia with respect to active ingredient Inertness to packaging (no interaction between container/content) Inertness to the body (neither clean nor toxicity share) 14 Route of administration
Percutaneous route
Local route SUBLINGUAL
INHALER
NASAL
VAGINAL
INTRASPINAL 15 Pharmaceutical Forms
Rectal Administration: Suppositories Local application: ointment, cream, Eye drops
16 Parenteral
Administration with syringe and needle Intravenous Injection:
intra-arterial Injection
Subcutaneous Injection
Intradermal Injection
Intramuscular Injection 17 Oral route: Anatomy
Absorption is the process by which the unchanged drug is excreted from its site of administration to the systemic circulation (measurement site)
18 Different barriers in oral absorption
Mouth: rapid absorption without first pass hepatic effect; dissolution in saliva Stomach (1m² area): Few drugs are absorbed, secretion of pepsinogen and HCl. Small intestine + colon (200-300m ² area): duodenum: Site digestion jejunum, ileum and colon: absorption sites very large exchange surface (Micro-vili the small intestine) Different secretion: mucus, digestive enzymes (such as lipase, amylase, esterase), trypsinogen, chymotrypsinogen, etc ... bicarbonate Pancreas: no absorption Gallbladder: secret synthesized which contains electrolytes bile and bile acids that help emulsify fat and increase the solubility of the fatty acids 19 Oral route: different barriers and different milieu (2)
20 Factors related to the GI tract
Digestive pH The rate of gastric emptying and intestinal motility Food Co-administration of drugs Age Other variations : pregnancy, physical exercise Co-morbidity factors : heart failure, severe hypotension, inflammatory process
21 Oral Bioavailability
Bio-availability: amount of the dose who reaches the blood circulation. 22 Drug resorption depends on:
Drug molecule cross the natural barrier (cytoplasm membrane). The rate of absorption depends on : 1. Physico-chemical properties which control the balance Hydrosolubility/ liposolubility (hydrophilicity/lipophilicity) 2. Chemical Nature (Size and morphology), pKa and degree of ionization. 3. Partition Coefficient (solubility nOctanol/water) 4. Morphology and crystallization form : micronized powder of Theophyllin 5. Pharmaceutical Form : controls the dissolution rate in the GI tract 23 How to cross biological barriers
Enterocytes show tight gap with microvillosity. Several process are involved 1. Passive diffusion : 2. Active transport 3. Facilitated diffusion 4. Filtration (like renal elimination)
24 PASSIVE DIFFUSION
Transmembrane cross with Fick equation: Rate of diffusion = DKsS (Cm-Cf)/E D: constante of diffusion S: surface (area )of exchange Ks: Partition Coefficient Cm - Cf : différence de concentration ; E = épaisseur (thickness) Diffusion depends on concentration gradient. It is a non-saturable process with no specificity. Passive diffusion depends on balance hydro/liposolubility and the amount of the non-ionic form. 25 Drug ionization degree is related to gastro-intestinal pH
26 Active transport of drugs
Specific Transporter of a given substance or substance type
Transporter can be saturated, Possibility of competition between similar drugs Energy is required
Against concentration gradient 27 Examples of active Transport 1. Endogenous carriers enable transport of ionized molecules, high molecular weight or of low lipophilicity. 2. This is the case of the system LNA (large neutral amino acids) that allows the entry of certain amino acids and structurally similar drugs such as L-Dopa, melphalan, Gabapentin. 3. The levodopa, Baclofen (Lioresal ®) which is a central muscle relaxant and phosphonoformate (antiviral) use the same carrier. 4. We can also mention the Glut-1 glucose transporter non-insulin-dependent, which can also carry certain glycopeptides. 28 FACILITATED DIFFUSION
Facilitated Diffusion ≠ passive diffusion : Rate of absorption is > concentration gradient Possible Transporter
29 P Glycoprotein or P-Gp
Efflux Protein, belongs to ABC transporters (« ATP Binding Cassette proteins ») : ex. P-Gp (glycoprotéine P = ABCB1)
30 12/12/2014 31 Oral route is forbidden
1. If the molecule is destroyed in gastric juice Penicillin G 2. Peptide like structure : Insulin 3. Drugs extensively metabolized 4. Unconscious patients
32 Oral Bioavailability
Bioavailability is the amount of drug who reach the blood (percentage of blood level/ administered dose) Determined by comparison to IV administration (IV = 100% of bioavailability) F= AUC (f.o) / AUC (f.iv)
33 Pharmacokinetic II DISTRIBUTION
34 2nd step: Distribution
35 DISTRIBUTION The whole body can be considered as set of organs (aqueous compartments) separated by cell membranes (Phospholipid). The passage of the drug from one compartment to another depends on its physicochemical properties (lipophilicity, pK ...). Thus, the drug must be soluble in the aqueous phase to stay while to spread from one compartment to another, it must be soluble. For example for a body weight of 70 kg = approximately 42 liters of total water of the body which is = 60%.
36 Apparent Volume of distribution
Volume of distribution is virtual (imaginary) volume wherein all of the drug is distributed in the same concentration as in plasma. It helps to calculate the dose in order to obtain the appropriate concentration at the site of action. When VD is large, there is a significant tissue distribution. When VD is small, the distribution is preferably plasma
37 Dose 10 mg
Volume réel 500 ml
Sans charbon Avec charbon
Concentration 20 mg/l Concentration 2 mg/l Volume apparent 500 ml Volume apparent 5000 ml
VD > 0,6 L.kg-1 forte diffusion VD < 0,3 L.kg-1 faible diffusion
38 Examples
VD values do not correspond to a physiological entity
39 How does the drug circulate in the blood? Liaison drug-protein is REVERSIBLE
Unbound fraction + plasma protein Protein Bound fraction (Unbound fraction fu) (Bound Fraction)
Active Form (pharmacology) Inactive Form (pharmacology), (no tissue diffusion) Loi d’action de masse: Médicament libre + protéine plasmatique Médicament lié à la protéine 40 Plasma proteins involved: -Albumin -α1glycoprotein acid -Lipoproteins -γ globulin -Transcortin
41 Drug-Drug Interactions : consequence of binding-unbinding plasma protein on distribution volume.
42 Factors modifying VD
Obese patients : increase VD for very lipophilic drugs: Diazepam, Thiopental Hydro-electrolytic disturbances, elderly patients Modifications of natural barriers : placenta, blood-brain barrier
43 Natural Barrier
44 Blood-Brain Barrier
45 Distribution in the CNS The brain capillary membrane is lined with a fabric of glial astrocytes support, thus creating a double barrier - glial membrane and capillary endothelium – very few hydrophilic molecules can cross BBB. The cerebral capillaries are formed of closely contiguous endothelial cells, devoid of intercellular pores and fully covered with cellular elements, mainly of astrocytes. The transcellular penetration appears to be the most plausible The flow of cerebrospinal fluid is the only limiting factor for the diffusion of lipophilic molecule 46 Placenta barrier
Placenta = organ of exchange of substances between mother and fetus. The placental diffusion is from the mother to the embryo through the placental barrier. The soluble and non-ionized molecules easily cross the barriers encountered three, namely: The trophoblastic epithelium, The mesenchymal tissue and The vascular endothelium 47 Fetal compartment 4 compartments: 1. Fetal blood 2. Extravascular fluid 3. Umbilical cord 4. Amniotic fluid.
48 Mechanism involved The mechanism of exchange through the placenta is essentially a process of passive diffusion. Active transport and facilitated diffusion exist for endogenous substances but not to exogenous substances. The Fick's law applies also in this case: Diffusion rate = DKsS (Cm-Cf) / E D: diffusion constant S: exchange surface Ks: Partition coefficient between the placental barrier and the external phase Cm - Cf: concentration difference between the mother and the fetus. E: Thickness The drug is then distributed to the fetus. The affinity of the drug for fetal tissue is often the same as the mother in late pregnancy but it is different in the first month of pregnancy. After metabolism, metabolites return to the mother through the umbilical arteries 49 Drugs in lactation
Questions: 1. Does the drug taken by the mother passes into breast milk? 2. In what concentration (we found it in children)? 3. What is the amount of milk drunk? (150ml/kg/day)
Incomplete responses for most drugs!
50 Références
Drugs in Pregnancy and Lactation, 9th Edition G.G. Briggs, R.K. Freeman, and S.J. Yaffe Lippincott Williams & Wilkins
51 Metabolism and renal elimination Clearance
The concept of clearance (English word) was introduced in 1973 by Rowland in pharmacokinetics, it is used to describe the removal of a substance: either by whole body (total body clearance) or by cleansing organs (renal clearance, hepatic, ...). These different mechanisms of elimination are additive (additive clearances), they contribute to the elimination from the body (total clearance).
53 Clairance: additive
Cl totale = Cl hépatique + Cl rénale + …. = ΣCl partielles
54 Equation
The clearance (CL) indicates the ability of an organ to completely purify a volume of fluid per unit of time. The clearance unit is generally l.h-1 or ml min-1. There are different clearances (according to the purified fluid, or organ so the mechanisms involved are multiple). Its value can not exceed the maximum value of the flow : E = 1 Cl=Q
55 Concepts et définitions Q = Blood flow in the organe Ca = concentration afférente (artérielle) Cv = concentration efférente (veineuse)
56 Metabolism
Metabolism is a part of the elimination process of a drug. The metabolism of a drug corresponds to the transformation by an enzymatic reaction of a drug to one or or more compounds, said metabolites. Metabolites may be pharmacologically inactive or pharmacologically sometimes toxic. Hydroxylation is the most frequent biotransformation. 57 General Metabolic Pathways
Oxidation Hydrolytic Reactions Aromatic moieties Esters and amides Olefins Epoxides and arene oxides Benzylic & allylic C atoms by epoxide hydrase and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system Phase II - Phase I - C-N (N-dealkylation, N-oxide Conjugation formation, N-hydroxylation) Functionalization C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration) Drug Oxidation of alcohols and Metabolism aldehydes Miscellaneous Reduction Glucuronic acid conjugation Aldehydes and ketones Sulfate Conjugation Nitro and azo Glycine and other AA Miscellaneous Glutathion or mercapturic acid Acetylation Methylation 58 Métabolisme (2)
Phase I Phase II
Introduction ou exposition Réactions de conjugaison d’un groupe réactif
hydrosolubilité
The result is the production of a conjugated derivative highly hydrosoluble (more polar) which makes possible its elimination by the kidney,
59 The aim of the metabolism step
60 Active/inactive metabolite
It is important to note that drug metabolism does not necessarily lead to its inactivation. Thus, prodrugs (or pro-drugs) are pharmacologically inactive, they are rapidly metabolized to the pharmacologically active metabolites.
61 Metabolite Examples and notes activity Inactive Routes that result in the formation of inactive metabolites are often referred to as detoxification. (detoxification) OH O O Phenol sulphokinase S O OH 3'-Phosphoadenosine-5'- Phenol phosphosulfate (PAPS) Phenyl hydrogen sulfate Similar activity The metabolite may exhibit either a different potency or duration of action or both to the original drug. CH3 CH to the drug O 3 O H O N N N Hydroxylation N-Demethylation OH OH Cl N Cl N Cl N Ph Ph Ph Diazepam Temazepam Oxazepam (Sustained anxiolytic action) (Short duration) (short duration)
CH3 CONHNHCH CONHNH2 Different CH3 N-Dealkylation activity N N Ipronazid Isoniazid (Antidepressant) (Antituberculosis) HO NCOCH3 NHCOCH3 NH2
Other substances responsible for Substances responsible Toxic hepatotoxicity for methemoglobinamia metabolites OC2H5 OC2H5 OC2H5 N-Hydroxyphenacetin Phenacetin Phenetidine (Hepatotoxic) (Analgesic) 62 Enzymes Involved in Drug Metabolism
CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases
Cytochrome P450 system: localized in the smooth endoplasmic reticulum. Simplified apoprotein portion Cytochrome P450 is a Pigment that, with CO bound to the reduced form, absorbs maximally at 450nm L CH3 CH3 HOOC Cytochromes are hemoproteins (heme-thiolate) that N N CH2 function to pass electrons by reversibly changing the Fe+3 oxidation state of the Fe in heme between the 2+ and 3+ N N CH3 state and serves as an electron acceptor–donor HOOC CH3 CH2
P450 is not a singular hemoprotein but rather a family O of related hemoproteins. Over 1000 have been H R identified in nature with ~50 functionally active in Substrate binding site humans with broad substrate specificity Heme portion with activated Oxygen
63 Cytochrome P450: Naming
■ Before we had a thorough understanding of this enzyme system, the CYP450 enzymes were named based on their catalytic activity toward a specific substrate, e.g., aminopyrine N-demethylase now known as CYP2E1 ■ Currently, all P450’s are named by starting with “CYP” (CYtochrome P450,
N1, L, N2 - the first number is the family (>40% homology), the letter is the subfamily (> 55% homology), and the second number is the isoform. The majority of drug metabolism is by ~10 isoforms of the CYP1, CYP2 and CYP3 families in humans ■ Major human forms of P450: Quantitatively, in the liver the percentages of total P450 protein are: CYP3A4 – 28%, CYP2Cx – 20%, CYP1A2 – 12%, CYP2E1 – 6%, CYP2A6 – 4%, CYP2D6 – 4% ■ By number of drugs metabolized the percentages are: CYP3A4 – 35%, CYP2D6 – 20%, CYP2C8 and CYP2C9 – 17%, CYP2C18 and CYP2C19 - 8% CYP 1A1 and CYP1A2 -10%, CYP2E1 – 4%, CYP2B6 – 3%
64 Few Important CYP450 Isozymes
CYP Main functions family CYP1 Xenobiotic metabolism CYP2 Xenobiotic metabolism, Arachidonic acid metabolism CYP3 Xenobiotic and steroid metabolism CYP7 Cholesterol 7α-hydroxylation CYP11 Cholesterol side-chain cleavage, Steroid 11β – hydroxylation, Aldosterone synthesis CYP17 Steroid 17α-hydroxylation CYP19 Androgen aromatization CYP21 Steroid 21-hydroxylation CYP24 Steroid 24-hydroxylation CYP27 Steroid 27-hydroxylation
65 EC Recommended name Family/gene 1.3.3.9 * secologanin synthase CYP72A1 1.14.13.11 * trans-cinnamate 4-monooxygenase CYP73 1.14.13.12 * benzoate 4-monooxygenase CYP53 1.14.13.13 * calcidiol 1-monooxygenase CYP27 1.14.13.15 * cholestanetriol 26-monooxygenase CYP27 1.14.13.17 * -monooxygenase CYP7 1.14.13.21 * flavonoid 3'-monooxygenase CYP75 1.14.13.28 * 3,9-dihydroxypterocarpan 6a-monooxygenase CYP93A1
1.14.13.30 * leukotriene-B4 20-monooxygenase CYP4F 1.14.13.37 * methyltetrahydroprotoberberine 14-monooxygenase CYP93A1 1.14.13.41 * tyrosine N-monooxygenase CYP79
66 Drug Interactions & Metabolism
The drug interactions depend upon: a) the isoform(s) required by the drug in question, b) the isoforms altered by concomitant therapy, c) the type of enzyme alteration (induction or inhibition).
67 General Metabolic Pathways
Oxidation Hydrolytic Reactions Aromatic moieties Esters and amides Olefins Epoxides and arene oxides Benzylic & allylic C atoms by epoxide hydrase and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system C-N (N-dealkylation, N-oxide Phase II - Phase I - formation, N-hydroxylation) Conjugation C-O (O-dealkylation) Functionalization C-S (S-dealkylation, S-oxidation, desulfuration) Oxidation of alcohols and Drug aldehydes Metabolism Miscellaneous Reduction Glucuronic acid conjugation Aldehydes and ketones Sulfate Conjugation Nitro and azo Glycine and other AA Miscellaneous Glutathion or mercapturic acid Acetylation Methylation 68 Tetrahydrocannabinol (D1-THC) Metabolism
7 CH3 CH2OH COOH 1 6 2 OH OH 3 OH 5 4
H3C H3C H3C O C5H11 O C H O C H CH3 5 11 5 11 CH3 CH3 1 1 D -THC 7-Hydroxy-D -THC D1-THC-7-oic Acid
COOR
OR COO- Where R = O OH H3C OH O C5H11 HO CH3 H Glucuronide conjugate at either -Glucuronyl COOH or phenolic OH group moiety
The metabolite is polar, ionisable and hydrophilic 69 Oxidative Reactions
Benzylic, allylic Arenols Arene Oxides OH aliphatic C O Hydroxylation Epoxides O C OH C C C H C C R N H R N OH
Miscellaneous "Activated Oxigen" 3+ R N CH R R NH + O CHR Oxidations [FeO] 2
S C R O CH3 R N R N O S P S CH3 O C R OH O O-Dealkylation N-Hydroxylation O P SH, S CH3 N-Dealkyaltion and Desulfuration S-Dealkylation Oxidative Deamination and S-Oxidation N-Oxide Formation
70 Aromatic Hydroxylation
R1 R1 R1
CYP450 Spontaneous
O ■ Mixed function oxidation of arenes to OH arenols via an epoxide intermediate R1 R1
arene oxide EEpoxidepoxide hy Hydrasedrolase Aromatase
■ Major route of metabolism for drugs with OH OH phenyl ring OH OH
■ Occurs primarily at para position R1 ■ Substituents attached to aromatic ring Glutathione influence the hydroxylation OH S ■ Activated rings (with electron-rich Glutathione
substituents) are more susceptible while R1
deactivated (with electron withdrawing Macromolecule + groups, e.g., Cl, N R3, COOH, SO NHR) are generally slow or OH 2 Macromolecule resistant to hydroxylation 71 Exemple de réaction de biotransformation (2)
L’hydroxylation étant la transformation la plus fréquente. Des désaminations, déshalogénations, désulfurations, époxydations, peroxygénations et réductions peuvent aussi faire partie de cette première étape.
72 Exemple de réaction de biotransformation (3)
73 Applications
Forme Forme(s) dans le forme exemples administrée compartiment central éliminée S S S pénicilline G, lithium
S S M M barbituriques
S S M M benzodiazépines
S S M M aspirine (« pro-drug »)
S M M M salazopyrine
S S M1 tox M2 M2 paracétamol substance initiale forme active forme toxique 74 Sites of Metabolization
Major organs and tissues involved in xenobiotic biotransformation : Mainly the liver: Hepatocytes contains a high concentration of biotransformation enzymes. Sometimes the kidney, Digestive tract (Duodenum, intestin), Lungs, Skin, Plasma enzymes …
75 Cycle catalytique du cytochrome P-450
Autres réactions : C > A réduction RH > RH.- D > B production de .- superoxyde O2
E > B production de H2O2
Formation potentielle de toxiques !
76 Phase II Reactions The use of a functional group to form a covalent bond with a highly soluble molecule: conjugation with glucuronic acid conjugation with sulfate acetylation (from acetyl-Co-A) conjugation with cysteine or glutathione (tripeptide with cysteine) or other amino acids, glycine, glutamine, taurine methylation (from the S-adenosyl donor) methionine: (eg. Inactivation reaction of catecholamines by COMT)
77 Exemples de Phase II
78 Les cytochromes P-450 ou monooxygénases microsomiales Famille complexe de protéines membranaires, généralement associées au réticulum endoplasmique, qui contiennent un groupe prosthétique hème.
12 grandes familles de cytochrome P450 : CYP1 ...CYP12
Les familles CYP1, CYP2 et CYP3 sont les principales concernées par le métabolisme des médicaments (d’autres sont impliquées dans la synthèse ou le métabolisme des stéroïdes ou des acides gras et dérivés).
79 Cytochromes P450 : exemples CYP1A1/2 : chez l’homme CYP1A2 dans le foie, CYP1A1 dans d’autre tissus, époxydation des hydrocarbures aromatiques polycycliques Induit par hydrocarbures aromatiques polycycliques CYP 2C9/19: responsables de la métabolisation du Clopidogrel, de la phénytoïne (C19), de la Coumadine et des AINS (C9). Inhibé par l’Oméprazole. CYP2D6 : responsable de la biotransformation du propranolol et de nombreux antiarythmiques. Inhibé par la quinidine. CYP2E1 : oxydation de l’éthanol (à côté de l’alcool déshydrogénase), induit par l’éthanol, activation toxique du paracétamol, chloroforme, etc. CYP3A4 : le CYP le plus abondant dans le foie humain, métabolise de très nombreux médicaments et des stéroïdes endogènes p. ex. : ciclosporine, érythromycine, ... . Nombreuses substances inhibitrices : ciméthidine, kétoconazole, .... CYP4A9/11: métabolisme des acides gras et dérivés (prostaglandines,
leukotriènes, thromboxanes) 80 Cytochromes P450 : importance pour les médicaments à usage clinique
81 Causes de variation du métabolisme des xénobiotiques
1. Induction (médicaments, composants alimentaires, } contaminants de l’environnement) 2. Inhibition 3. Polymorphisme génétique. 4. Âge 5. Pathologie
82 Variabilité d’ordre pharmacocinétique
Variabilité des concentrations plasmatiques individuelles de phénytoïne
Taux plasmatiques en fonction de la dose orale journalière en mg/kg
83 Induction Augmentation potentiellement très importante de l’activité de systèmes métaboliques (P-450 surtout, mais aussi enzymes de phase II) par de nombreux médicaments, hydrocarbures aromatiques polycycliques, insecticides, stéroïdes, etc. C R L’induction apparaît en un ou quelques jours et nécessite la synthèse de nouvelle protéines par stimulation de la transcription. Cette induction est commandée par l’occupation d’un récepteur intracellulaire; par ex. récepteur à la exemple : induction du CYP3A6 par la rifampicine (R) dioxine ou aux hydrocarbures (microsomes hépatiques de lapin) aromatiques (Ah receptor). 84 Induction: exemples Phénobarbital : induction du CYP3A mais aussi nombreux autres Conséquences de enzymes hépatiques, amplification l’induction : Accélération du RE. Activation peu spécifique du considérable de la vitesse métabolisme hépatique de d’élimination de toutes les nombreuses substances. substances métabolisées par Benzopyrène: stimulation très le système induit (demi-vie rapide et très importante du diminuée), médicaments CYP1A2 (époxydation du mais aussi hormones benzopyrène et d’autres endogènes hydrocarbures aromatiques mais aussi: formation polycycliques). accélérée de métabolites PCB (polychlorinated biphenyl) : toxiques ou carcinogènes induction du métabolisme des stéroïdes 85 Exemples de médicaments inducteurs des CYP-450
86 millepertuis (Hypericum perforatum)
Saint John’s87 wort Inhibition des cytochromes P-450 exemples Inhibition spécifique, par ex. du CYP-2D6 par la quinidine inhibition plus large (surtout CYP3A) par interaction avec l’hème (cimétidine, kétoconazole) compétition de deux substrats pour un même CYP = inhibition compétitive inhibition et induction peuvent coexister : ex. alcool
88 Exemple d’interaction La pravastatine et la simvastatine sont 2 inhibiteurs de l’HMG CoA réductase (statine) dont le mécanisme d’élimination diffère. La simvastatine a une faible biodisponibilité orale du fait d’un important effet de premier passage hépatique dépendant de l’activité du CYP3A4 ; La pravastatine n’est pas métabolisée et éliminée essentiellement par sécrétion biliaire. Lorsque qu’ils sont administrés en présence d’inhibiteurs du CYP3A4, les concentrations plasmatiques de simvastatine s’élèvent près de 20 fois alors que celles de la pravastatine, prise conjointement avec les mêmes inhibiteurs du CYP3A4 demeurent inchangées (puisque la pravastatine n’est pas éliminée par métabolisme). Pour chaque statine sont indiquées les Les conséquences de cette interaction concentrations sans inhibiteur (barre médicamenteuse pharmacocinétique par inhibition blanche), les concentrations en présence enzymatique sont une fréquence accrue de toxicité d’itraconazole (barres rouges) et les musculaire propre aux statines lorsque la concentrations en présence de jus de simvastatine est prise avec des inhibiteurs du pamplemousse (barres jaunes). 89 CYP3A4. Exemples de médicaments inhibiteurs des CYP-450
90 Autres causes de variabilité du métabolisme des médicaments
âge immaturité chez le nouveau-né ou prématuré, activité diminuée chez les personnes âgées. Ex. toxicité du chloramphénicol chez le nouveau né due à l’immaturité d’une estérase hépatique.
état physiologique ou pathologique du foie polymorphisme génétique
91 Renal Clearance 3 méchanisms contribute to renal elimination rénal : 1. Glomerular Filtration 2. Tubular Secretion 3. Tubular Reabsorption
92 Kidney function
Excretion of metabolic wastes Regulation of mineral and water balance Release of renin that is important in regulation of blood pressure and blood volume Release of erythropoietin in response to hypoxia; erythropoietin stimulates the production of red blood cells in the bone marrow.
93 La clairance rénale: formule
La clairance rénale est le volume de sang débarrassé d’une substance par unité de temps.
94 La clairance rénale Filtration Glomérulaire: Passage libre: PM< 68 000 Da Médicament libre (fu) non lié Clairance de filtration maximale: 120 ml/min Processus obligatoire pour les petites molécules Réabsorption tubulaire Processus non obligatoire pour un médicament, il concerne les molécules qui ont été filtrées Il permet le retour dans la circulation sanguine
Rôle majeur de la polarité 95 Sécrétion tubulaire
Processus non obligatoire pour un médicament Concerne les molécules qui n’ont pas (encore) été filtrées ou qui ont été réabsorbées Transport actif via transporteurs –Saturation –Compétition –Risque d’interactions médicamenteuses
96 Influence du pH sur l’ionisation
L’alcalinisation des urines favorise l’élimination de l’aspirine. La figure ci-dessous illustre bien la relation qui existe entre le débit d’élimination urinaire (ou clairance rénale) et le pH urinaire pour l’aspirine. Dans le cas d’un surdosage, il est possible d’augmenter l’élimination urinaire de l’aspirine en alcalinisant les urines.
97 La clairance rénale de la créatinine
Créatinine plasmatique stable, non liée aux protéines. Elle est filtrée, pas réabsorbée et très peu excrétée. Sa clairance plasmatique reflète la filtration glomérulaire.
98 T1/2 et Clairance La demi-vie plasmatique est le temps au bout duquel la moitié de la concentration plasmatique est éliminée. On peut dire aussi que c’est le temps nécessaire à la division par deux de la concentration plasmatique On peut démontrer que :
La T1/2 est donc fonction de la clairance et du Volume de distribution.
La T1/2 est une valeur constante déterminée de façon expérimentale.
99 La T1/2 est déterminée de façon expérimentale.
La demi-vie est caractéristique d’un médicament, elle est indépendante de la voie d’administration, de la dose ou de la forme pharmaceutique. 100 Paramètres Pharmacocinétiques
Volume of distribution V = DOSE / C0
Clairance Plasmatique Cl = Kel .Vd
T ½ plasmatique t1/2 = 0.693 / Kel
Dose = CL x AUC et Dose x F = CL x AUC
Biodisponibilité (AUC)x / (AUC)iv
101 Temps Fraction éliminée T ½ 50 % 2 x T ½ 75 % 3 x T ½ 87,5 % 4 x T ½ 94 % 5 x T ½ 97 % 6 x T ½ 98 % 7 x T ½ 99 % 8 x T ½ 99,6 % 9 x T ½ 99,8 %
102