It is stated that most clinical pharmacology studies in older persons have included small numbers of individuals who were healthy, under 70 to 75 years and were white. This application seeks to extend the study of age related pharmacokinetics and drug metabolism to include older persons, frail individuals, males and females, and minorities. Furthermore, it is proposed to examine the effect of diet on drug metabolism and clearance. The proposal has the following aims: 1) To determine the effects of race, gender, frailty, drug co-administration and diet on drug clearance in patients using population kinetic techniques. This will address numerous hypotheses including: a) That clearance of high first pass CYP3A substrate drugs such as verapamil and nifedipine but not amlodipine (multiple CYP pathway substrate with low clearance and low first pass metabolism) is decreased in African Americans compared to Caucasians; and b) Hypotheses related to effects of gender, clinical frailty (defined), other drugs and dietary intake will be tested in patients from outpatient clinics and extended care institutions. About 350 patients on each drug, with at least 100 subjects being frail, homebound or institutionalized, will be included. Extensive data will be collected in a systematic fashion from the subjects, including detailed dietary history. Blood sampling will be performed 2 - 12 h after dose for estimation of plasma concentrations of nifedipine, verapamil, norverapamil, and amlodipine by HPLC and GC/ECD. Protein binding will be performed using equilibrium dialysis. Population kinetics will be performed using NONMEM analysis with age, gender, frailty and other covariates added in stepwise fashion. 2) To determine the mechanism for race and gender differences in drug clearance. Traditional methods will be used to address the following hypotheses: a) Race affects oral but not iv clearance of nifedipine and verapamil due to effects of self selected diet in African American and Caucasian men and women; b) That standard diet thus will eliminate differences; c) That gut metabolism is the reason for racial differences (abolished by CYP3A gut inhibition) in bioavailability but not gender (not abolished by CYP3A gut inhibition) differences; d) Gender differences reflect higher hepatic and intestinal clearance in females; and e) Ethnic differences are related to diet and abolished by standard diet. Pharmacokinetic studies will be performed in young and older, healthy male and female, white and African American volunteers. Individuals will be given iv an oral nifedipine and verapamil under controlled conditions and blood sampling will be performed for drug/metabolite assays and pharmacokinetic analysis. As much as possible the same subjects will have oral pharmacokinetic studies of nifedipine and verapamil performed following grapefruit juice to block intestinal CYP3A. Further studies are planned to compare oral pharmacokinetics of verapamil and/ nifedipine in similar subjects on a standardized diet.
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