_of Intestinal Drug Absorption and Intestinal Drug 肠道药物吸收的审查和肠道药物课件.ppt

PHAR 751 Dietary Effects on Metabolism Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System sbrown@ Metabolism: P-gp review Substrate + Inhibitor = Substrate + Inducer = CYP Metabolism Cytochrome P450 Gene superfamily: families? subfamilies? enzyme Oxidative metabolism – Phase I Location Liver Small intestine Most abundant P450 is CYP3A4 Induction = Inhibition = Metabolism: CYP review Substrate + Inhibitor = Substrate + Inducer = Metabolism Diet Food Macronutrients Protein CHO Fats Micronutrients Vitamins Minerals Indoles Drink Grapefruit juice Orange juice Seville orange juice Alcohol ? Diet can alter enzyme activity ? influence the intensity duration of action Macronutrients: Protein Intake 20% of diet Malnutrition contributes to variability in drug metabolism CYP-mediated In rats: CYP3A activity ↓ from 18% to 1% w/ ↓protein intake CYP1A2 ↓ w/ 0.5% protein diet CYP1A1: no change Protein intake theophylline metabolism CYP-mediated ↓ in Cl of 30% when reduce protein intake from 20% to 10% ↓ t? from 8-9 h to 6 h by increasing protein from 10% to 40%. TPN patients ? lower plasma Cl Another route of metabolism: FMO1 Flavin-containing monooxygenase (FMO) 1 protein Oxidative metabolism Non-inducible Influenced by dietary intake Micronutrient: Indole effect on metabolism Indole-3-carbinol (I3C) Naturally-occurring chemical found in cruciferous vegetables Induces CYP1A1 Inhibits FMO1 Also marketed as dietary supplement Influence of dietary I3C on FMO1 protein levels FMO (-) and CYP (+) Micronutrient: Indole effect on metabolism of tamoxifen Why do we care? Clinical relevance Drug-drug or drug-food interactions Potential for altered toxicity of drugs that are substrates for FMO and CYP Potential altered efficacy (i.e. tamoxifen) I3C DIM dietary supplements Alcohol Tobacco effects on metabolism 80 – 95% alcoholics smoke (25 – 30% non-alcoholics smoke) 70% are heavy smokers Those who drink smoke ? more cigarettes/day Correlation be