Drug Disposition Overview - Pharmacology and at UCSD

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BIOM/PHAR 255 Winter 2013 Halpert - Jan. 17, 2013 Mechanisms of P450 Inhibition •Alternate substrate inhibition •Binding of nitrogen heterocycles to heme iron (ketoconazole, itraconazole) •Binding of a metabolite to the reduced heme iron (troleandomycin, paroxetine) •Irreversible modification of the protein or heme moiety by a reactive metabolite (tienilic acid, ticlopidine, chloramphenicol) Factors affecting drug metabolism Enzyme induction: examples 12 of 22 Effect of fluovoxamine on caffeine pharmacokinetics (>10-fold increase in t 1/2 and AUC) Nuclear Receptors That Induce Drug Metabolism RECEPTOR LIGANDS • Aryl hydrocarbon receptor (AhR) • Constitutive androstane receptor (CAR) • Pregnane X receptor (PXR) • Farnesoid X receptor (FXR) • Vitamin D receptor • Peroxisome proliferator activated receptor (PPAR) • Retinoic acid receptor (RAR) • Retinoid X receptor (RXR) • Omeprazole, Flavonoids • Phenobarbital • Rifampin • Bile Acids • Vitamin D • Fibrates • all-trans-Retinoic acid • 9-cis-Retinoic acid
BIOM/PHAR 255 Winter 2013 Halpert - Jan. 17, 2013 Model for PXR in Xenobiotic Regulation Xenobiotic Pregnane X PXR RXR CYP3A gene “Other drug metabolism genes” Xenobiotic CYP3A Common Perpetrator Drugs HO-Xenobiotic Steroid HO-Steroid •Strong inducers of CYP3A4 (rifampicin, dexamethasone, phenobarbital, carbamazepine) •Strong inhibitors of CYP3A4 (ritonavir, ketoconazole) •Strong inhibitors of CYP2D6 (quinidine, fluoxetine, paroxetine) •Inhibitors of multiple P450 enzymes (fluvoxamine) Common Victim Drugs •Drugs with a narrow therapeutic index (warfarin, phenytoin, digoxin) •Substrates of CYP3A with low oral bioavailability (triazolam) 13 of 22 Why are clinically significant drug interactions relatively uncommon? •The interaction, while statistically significant, is too small to produce a clinically important change in the dynamics of the drug. •The therapeutic index of the victim drug is large enough that even a substantial change in plasma levels does not alter therapeutics or toxicity. •Kinetics and response to the victim drug are so variable that they overshadow changes in plasma levels due to the interaction. CYP dependent metabolism of drugs (80 % of all phase I metabolism of drugs) Beta blockers Antidepressants Antipsychotics Dextromethorphan Codeine Debrisoquine CYP2D6* CYP2C19* CYP2E1 CYP1A2 CYP2B6* CYP3A4/5/7 Cyclosporin Taxol Tamoxifen Tacrolimus Amprenavir Amiodarone Cerivastatin Erythromycin Methadone Quinine CYP2C9* Tolbutamide Warfarin Phenytoin NSAID Diazepam Citalopram Anti ulcer drugs Clozapine Ropivacaine Efavirenz Cyclophosphamide 40 % of the phase I metabolism is carried out by polymorphic P450s (enzymes in Italics)
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Drug Disposition Overview - Pharmacology and at UCSD

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