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Pharmacokinetics and Toxicokinetics Pharmacokinetics and Toxicokinetics Howard A. Greller, MD FACEP FACMT North Shore University Department of Emergency Medicine Division of Medical Toxicology WHAT WE’LL COVER TODAY • Pharmacokinetics/Toxicokinetics • Absorption • Distribution • Metabolism • Elimination • Pharmacodynamics/Toxicodynamics • Xenobiotic interactions • Pharmacogenomics/Toxicogenomics OVERVIEW Tissue Therapy Toxicity Absorption Elimination Dose Drug Excretion Liberation Metabolite Protein Biotransformation ABSORPTION •Process by which a xenobiotic enters body •Rate of absorption (ka) determined by: •Route of administration •Dosing form •Bioavailability ROUTE OF ABSORPTION •Affects rate and extent •IV, inhalation > IM, SQ, IN, PO> SQ, PR •Onset dependent on route ROUTE OF ABSORPTION Oral, onset approximately 20 minutes ROUTE OF ABSORPTION Smoking ~10 seconds, IV ~30 seconds DISSOLUTION DIFFUSION DISINTEGRATION EROSION OSMOTIC PUMPS ION EXCHANGE RESINS BIOAVAILABILITY •Amount reaches systemic circulation, unchanged •Extent of absorption •Predicts intensity of effect •First pass effects modify bioavailability FIRST PASS EFFECTS • Prevention of absorption • Decon / chelation (+/-) • P-glycoprotein • Bezoars, mod preps • Pre-systemic metabolism • Hepatic, gastric mucosa, intestinal BB • Bacterial • Saturable in overdose FIRST PASS EXAMPLES • Gastric emptying time • Food, medications • Gastric ADH • Age, sex, H2 • “worst case” • High FP (“low bioavailability”) • Propranolol, cyclosporine, morphine, TCAs IONIZATION • Uncharged, non-polar cross membranes • pH + pKa (dissociation constant) determine ionization (HH) - • Log (HA/A ) = pKa - pH • HA/A- = 10pKa-pH - • pH < pKa ➡ HA/A > 1 • Favors non-ionized - • pH > pKa ➡ HA/A < 1 • Favors ionized SALICYLATE • Weak acid (pKa 3.5) Brain Blood Urine pH ~ 6.8 pH ~ 7.4 pH variable SH SH SH H+ + S- H+ + S- H+ + S- What is HA/A- in urine for pH=3.5? 7.5? ION TRAPPING •HA/A- = 10pKa-pH •pH 3.5 = (103.5-3.5) = 100 = 1 = 1:1 •pH 7.5 = (103.5-7.5) = 10-4 = 1/10,000 •With alkalinization, ionized, “trapped” LIPID SOLUBILITY • Partition coefficients (oil/water) • Higher lipid solubility, higher absorption • Even with similar pKa • Thiopental >> secobarbital >> barbital • All with pKa of ~7.8 SURFACE AREA •Affected by blood flow •Hypotension •Vasoconstriction SPECIALIZED TRANSPORT • Active (energy dependent) • Transport against a concentration gradient • Facilitated (energy independent) • Xenobiotics utilize native systems • 5-FU resembles pyrimidine • Thallium/Pb resemble K+ and Ca2+ P-GLYCOPROTEIN (PGP) • Active efflux transporter (inside out) - “ABC” family • BBB, BTB, brush border Digoxin, protease inhibitors, vinca alkaloids, S paclitaxel Amiodarone, ketoconazole, quinidine, verapamil St. John’s wort DISTRIBUTION VOLUME OF DISTRIBUTION • Where the drug goes • Vd (L/kg) = amount/Cp = SxFxdose/C0 [C]=(S x F x dose)/(Vd x kg) • Apparent proportionality constant • Not a real volume (i.e. chloroquine ~185 L/kg) SOME EXAMPLES Large Vd (>1 L/kg) Small Vd (<1 L/kg) • Antidepressants • Alcohols • Camphor • Lithium • Digoxin • Phenobarbital • Opioids • Phenytoin • Phencyclidine • Salicylate • Phenothiazines • Valproic acid ONE COMPARTMENT MODEL Change in [plasma] = change [tissue] Ka Vd Ke TWO COMPARTMENT MODEL • Measure #1 • Effects in #2 • Examples K a • Digoxin k 12 #2 • Lithium k21 • There can be multiple, multiple #1 compartments . Ke MODIFIERS •Lavage, AC and WBI ⬇Ka •MDAC, ion-trapping, chelation ⬆Ke •Decrease Cmax, tmax and AUC •Extracorporeal techniques ⬆Ke DISTRIBUTION ≠ SITE OF TOXICITY / ACTION •Lead ➡ bone •CO ➡ Hgb vs •DDT ➡ fat •Paraquat ➡ type II alveolar PROTEIN BINDING • Phenytoin 90% bound with normal albumin • Albumin decreases, more free active drug • [phenytoin] = 14 mg/L (10-20 mg/L) • Sick (2 g/dL) vs. Healthy (4 g/dL) • [adjusted] = [measured] / ((0.25 x albumin) + 0.1) • 23.33 mg/L vs. 12.73 mg/L PROTEIN BINDING - ASA •Overdose increases apparent Vd •⬆ free drug ➞ lower pH ⬆ HA ⬆ diffusion •More drug in tissues, more toxicity •Other drugs with high protein binding •Carbamazepine, valproate, warfarin, verapamil POOR LITTLE JOHNNY . • Johnny got dumped • He went home and took grandma’s digoxin • Grandma calls poison control • Do we have to be worried? • Johnny weighs 50 kg • Grandma’s pills are 250 mcg each • There were 25 of them left . WORST CASE SCENARIO . • [C] = (S x F x dose) / (Vd x kg) = (1 x 0.7 x 25 x 0.25mg) / (6 L/kg x 50kg) = (4.38mg) / (300L) = 0.015mg/L • Units, units, units . = (0.015mg/L) x (106ng/mg) x (1L/1000mL) • [digoxin] = 15 ng/mL (worry) HOW MUCH FAB? • TBL (total body load) = S x F x dose • 1 x 0.7 x (25 x 0.25 mg) = 4.375 mg • Each vial binds 0.5 mg digoxin • Therefore, need 9 vials based on dose • Worst case ([C] x kg)/100 = 8 vials (round up) HIS LEVEL IS 4 NG/ML . • Dose = Vd x Cp; Vd = 6 L/kg; wt = 50 kg; 0.5mg digoxin bound / vial Dose = (6 L/kg) x (50 kg) x (4 ng/mL) = 1200 . 1200 what? (103 mL/1 L) x (6 L/kg) x (50 kg) x (4 ng/mL) x (1 mg/106 ng) = 1.2 mg • 0.5 mg/vial = 3 vials (round up) • Shorthand ([C] x kg)/100 = 2 vials METABOLISM METABOLISM • “Morally” neutral • Toxicate vs detoxify vs biotransform • LEO GER (CYP 450) • Oxidize substrate (lose e-) • Reduce electrophile (gain e-) • Cyclical oxidation co-factor • i.e. NADH / NAD+ • Links catabolism to synthesis PHASE I (PREPARATORY) • Add/expose polar groups •HHydrolysis • Esterase, peptidase, epoxidase •OOxidation • P450, ADH, MAO, etc. •RReduction • Azo-, Nitro-, Carbonyl-, Quinone •DeDe-alkylation (A1) Carboxylic acid ester (delapril) (A2) Carboxylic acid ester (procaine) O NH2 NH2 C OC2H5 O O H2O H2O N CH CH NH CH CNCH COOH C OH C H OH + 2 2 2 + 2 5 HO hCE1 hCE2 CH3 R N C O COOH O (B) Amide (procainamide) (C) Thioester (spironolactone) O O NH2 NH2 O O H2O H O + N 2 H N + CH3COOH N 2 C NH PHASE I EXAMPLESCOOH O O SCOCH3 O SH (D) Phosphoric acid ester (paraoxon) + + (E) Acid anhydride (diisopropylfluorophosphate) CH3CH2OH + NADPH + H + O2 CH3CHO + NADP + 2H2O CYP2E1 O C2H5 O P O C2H5 O OH O O H O CH3 CH3 2 CH3 CH3 + O + CH OP OCH CH OP OCH + HF CH3CH2OH + NAD H 2 O CH3CHO + NADH + H CH3 CH3 CH3 CH3 C H F OH Alcohol Dehydrogenase + 2 5 OP OC2H5 hPON1 OH NO2 NO2 (F) Transesterification (cocaine) (G) Lactone (spironolactone) O methyl ester ethanol ethyl ester COOH O CH CH OH O 3 2 O OH H3C COCH H C 3 3 C OCH2CH3 N N H2O O hCE1 O hPON3 OC OO CH3OH methanol SCOCH O SCOCH3 O 3 Casarett & Doull’s 7th Edition (H) Phosphate prodrugs (fosamprenavir) OH OH O P OH O H O 2 H H O N N NH2 + H PO O N N NH2 3 4 Alkaline Phosphatase O S O S O O O O O O Figure 6-4. Examples of reactions catalyzed by carboxylesterases, cholinesterases, organophosphatases, and alkaline phosphatase. hCE1 and hCE2, human carboxylesterases 1 and 2; hPON1 and hPON3 (human) paraoxonase 1 and 3. PHASE II (SYNTHETIC) •Conjugation polar groups •⬆ hydrophilicty •Glucuronide, acetate, sulfate, methyl, amino acids and glutathione •GAS MAG CYP 450 INTERACTIONS Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007) http://medicine.iupui.edu/clinpharm/ddis/table.aspx Accessed 3/2012 CYP 1A2 Inducers broccoli'&'brussel'sprouts,' Aryl Hydrocarbon Hydroxylase cigare,es,'char1grilled'meat,' 15% pharmaceuticals insulin,'modafinil,'omeprazole Linked with cancer Inhibitors Substrates fluvoxamine,6ciprofloxacin6 • Caffeine amiodarone,'cime8dine,' • Carvedilol clarithromycin,'interferon,' • Clozapine 8clodipine • Theophylline Toxica9on • R-warfarin • APAP APAP,'benzo[a]pyrene,' • Haloperidol dichloromethane CYP 2C9 Inducers rifampin,'secobarbital Most abundant CYP2C Inhibitors Substrates •NSAID’s fluconazole,6amiodarone,' •S-warfarin fluvoxamine,'isoniazid,'lovasta8n,' sertraline,'sulfamethoxazole •Sulfonylureas •Phenytoin Toxica9on •ARBs Phenytoin'&'warfarin'(decreased' metabolism) Inducers CYP 2C19 Absent 20% Asians carbamazepine,'prednisone,' “PPIs & Seizures” rifampicin Substrates Inhibitors •Diazepam omeprazole,6cime8dine,' fluoxe8ne,'indomethacin,' •Phenytoin ketoconazole,'modafinil,' •Phenobarbital oxcarbazepine,'8clodipine,' topiramate •Omeprazole Toxica9on •R-warfarin •Carvedilol CYP 2D6 Inducers 25% drugs, 50% antipsych dexamethasone,'rifampin 10% W, 8% AA poor metab Ethiopian ultra-rapid metab Inhibitors Substrates bupropion,6fluoxe9ne,6 •β-blockers paroxe9ne,6quinidine,6sertraline,' •Codeine duloxe-ne,'amiodarone,' •Methadone, oxycodone, cime8dine,'citalopram,'cocaine,' codeine doxorubicin,'h1'antagonists,' •Tamoxifen methadone,'metoclopramide,' •TCAs, SSRIs ritonavir, •Haloperidol Toxica9on CYP 2E1 Inducers ethanol6(chronic),'fomepizole,' 7% total CYP in liver isoniazid,'phenobarbital,' Only other CYP cancer phenytoin,'cigareGe'smoke (1A2) Inhibitors •NP CA in Chinese smokers disulfiram,'diethyl1 dithiocarbamate,'ethanol'(acute),' Substrates fomepizole •Acetaminophen Toxica9on •Anesthetics acetaminophen,'ifosphamide,' •Ethanol acrylonitrile,'CCl4,'aniline,' benzene,'dichloromethane,'vinyl' •Theophylline chloride Inducers CYP 3A4 • Most abundant CYP in liver carbamazepine,'efavirenz,' • Most common intestinal modafinil,'glucocor8coids,' • 50-60% all pharmaceuticals oxcarbazepine,'phenobarbital,' • Terfenadine + erythromycin phenytoin,'rifampin,'st.'john’s'wort Substrates Inhibitors protease6inhibitors,6clarithromycin,6 ketoconazole,6erythromycin,3 fluconazole,3grapefruit3juice,3 verapamil,3dil-azem,3cime8dine,' amiodarone.'ciprofloxacin,' fluvoxamine,'starfruit Toxica9on acetaminophen,'aflatoxin Inducers P-GLYCOPROTEIN rifampin,'st.'john’s'wort Substrates Inhibitors •Cyclosporine •Digoxin amiodarone,'cyclosporine,'
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