The oral bioavailability of drugs if determined by their absorption from the gastro-intestinal tract and first-pass metabolism occurring in either the intestinal epithelium and/or the liver. The often marked interindividual variability in plasma concentrations and associated clinical response is frequently determined by these factors. Extensive study has been made of the hepatic component of this effect, but other determinants are largely undefined. For example, CYP3A-mediated metabolism during absorption by the intestinal epithelium and efflux from this tissue associated with P- glycoprotein. Such processes as well as metabolism in the liver may be potentially modulated by dietary-related factors and/or intestinal disease. Accordingly, studies will address some of these determinants that are important in the clinical use of drugs or may be significant in the chemoprevention of cancer resulting from dietary and environmental procarcinogens. In the latter instance, it is though that enzymes like CYP1A, CYP2E1 and CYP3A activate the procarcinogen. Since the chemoprotective effect of vegetables against cancer is well-recognized, it is hypothesized that certain phytochemical may inhibit these enzymes. This will be tested by investigating the ability of cruciferous vegetables and garlic-related products to inhibit the metabolism of in vivo probes of the individual CYP isoforms in humans. Subsequently, studies will be extended to examine the effects of representative pure chemical constituents that are under development as chemoprotective agents (oltipraz, phenethyl isothiocyanate, S-allyl cysteine). The effect of diet of CYP2E1 and CYP3A activities will also be examined in racial groups with different disposition characteristics from Caucasians, as identified in Project 1. In particular, Japanese and Mexican-Americans that routinely eat a """"""""western"""""""" diet compared to """"""""native"""""""" diet. The mechanism(s) whereby dietary salt affects the plasma concentration-time profile of certain CYP3A/P-glycoprotein substrates will also be examined in both humans and animal models. Finally, the effect of intestinal disease such as celiac disease and tropical sprue on the oral bioavailability of drugs will be determined, since such inflammatory diseases are associated with major disturbances in the structure and functioning of the intestinal epithelium.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM031304-17
Application #
6107500
Study Section
Project Start
1999-07-01
Project End
2000-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Johnson, Daniel H; Gebretsadik, Tebeb; Shintani, Ayumi et al. (2013) Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose. Br J Clin Pharmacol 75:997-1006
Kohli, Utkarsh; Pandharipande, Pratik; Muszkat, Mordechai et al. (2012) CYP2A6 genetic variation and dexmedetomidine disposition. Eur J Clin Pharmacol 68:937-42
Kohli, Utkarsh; Hahn, Maureen K; English, Brett A et al. (2011) Genetic variation in the presynaptic norepinephrine transporter is associated with blood pressure responses to exercise in healthy humans. Pharmacogenet Genomics 21:171-8
Ho, Richard H; Leake, Brenda F; Kilkenny, Dawn M et al. (2010) Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics 20:45-57
Kohli, Utkarsh; Muszkat, Mordechai; Sofowora, Gbenga G et al. (2010) Effects of variation in the human alpha2A- and alpha2C-adrenoceptor genes on cognitive tasks and pain perception. Eur J Pain 14:154-9
Muszkat, Mordechai; Kurnik, Daniel; Sofowora, Gbenga G et al. (2010) Desensitization of vascular response in vivo: contribution of genetic variation in the [alpha]2B-adrenergic receptor subtype. J Hypertens 28:278-84
Muszkat, Mordechai; Bialer, Omer; Blotnick, Simcha et al. (2010) Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults. Clin Ther 32:347-56
Li, Chun; Schwarz, Ute I; Ritchie, Marylyn D et al. (2009) Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood 113:3925-30
Haas, David W; Gebretsadik, Tebeb; Mayo, Gail et al. (2009) Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans. J Infect Dis 199:872-80
Kurnik, Daniel; Li, Chun; Sofowora, Gbenga G et al. (2008) Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade. Pharmacogenet Genomics 18:895-902

Showing the most recent 10 out of 351 publications