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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG015982-01A1
Application #
2902994
Study Section
Special Emphasis Panel (ZRG1-GRM (04))
Project Start
1999-09-01
Project End
2000-03-31
Budget Start
1999-09-01
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Schwartz, Janice B; Gallagher, J Christopher; Jorde, Rolf et al. (2018) Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations. J Clin Endocrinol Metab 103:3278-3288
Schwartz, Janice B; Moore, Kelly L; Yin, Michael et al. (2014) Relationship of vitamin D, HIV, HIV treatment, and lipid levels in the Women's Interagency HIV Study of HIV-infected and uninfected women in the United States. J Int Assoc Provid AIDS Care 13:250-9
Schwartz, J B; Lai, J; Lizaola, B et al. (2014) A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol Metab 99:1631-7
Schwartz, J B; Lai, J; Lizaola, B et al. (2014) Variability in free 25(OH) vitamin D levels in clinical populations. J Steroid Biochem Mol Biol 144 Pt A:156-8
Kane, Lynn; Moore, Kelly; Lütjohann, Dieter et al. (2013) Vitamin D3 effects on lipids differ in statin and non-statin-treated humans: superiority of free 25-OH D levels in detecting relationships. J Clin Endocrinol Metab 98:4400-9
Schwartz, Janice B; Kane, Lynn; Moore, Kelly et al. (2011) Failure of pharmacogenetic-based dosing algorithms to identify older patients requiring low daily doses of warfarin. J Am Med Dir Assoc 12:633-8
Schwartz, J B (2009) Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence. Clin Pharmacol Ther 85:198-203
Schwartz, J B; Verotta, D (2009) Population analyses of atorvastatin clearance in patients living in the community and in nursing homes. Clin Pharmacol Ther 86:497-502
Schwartz, J B (2007) The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther 82:87-96
Schwartz, Janice B (2006) Erythromycin breath test results in elderly, very elderly, and frail elderly persons. Clin Pharmacol Ther 79:440-8

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