Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B71c is associated with faster zidovudine clearance and glucuronidation

Awewura Kwara; Margaret Lartey; Isaac Boamah; Naser L Rezk; Joseph Oliver-Commey; Ernest Kenu; Angela D M Kashuba; Michael H Court

doi:10.1177/0091270009338482

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Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B71c is associated with faster zidovudine clearance and glucuronidation

Journal article

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Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B71c is associated with faster zidovudine clearance and glucuronidation

Awewura Kwara, Margaret Lartey, Isaac Boamah, Naser L Rezk, Joseph Oliver-Commey, Ernest Kenu, Angela D M Kashuba and Michael H Court

Journal of clinical pharmacology, Vol.49(9), pp.1079-1090

09/2009

DOI: https://doi.org/10.1177/0091270009338482

Handle:

https://hdl.handle.net/2376/105598

PMID: 19628728

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Abstract

Lamivudine - administration & dosage

Humans

Middle Aged

Tuberculosis - etiology

Zidovudine - pharmacokinetics

Half-Life

Male

Stavudine - administration & dosage

Reverse Transcriptase Inhibitors - administration & dosage

Drugs, Generic - therapeutic use

Zidovudine - administration & dosage

Glucuronosyltransferase - genetics

Reverse Transcriptase Inhibitors - pharmacokinetics

Glucuronides - metabolism

Drugs, Generic - pharmacokinetics

Stavudine - therapeutic use

Tuberculosis - drug therapy

Lamivudine - therapeutic use

Adult

Female

Reverse Transcriptase Inhibitors - therapeutic use

Drug Therapy, Combination

Liver - metabolism

AIDS-Related Opportunistic Infections - drug therapy

Ghana

Lamivudine - pharmacokinetics

Polymorphism, Genetic

HIV Infections - complications

HIV Infections - drug therapy

Zidovudine - therapeutic use

Stavudine - pharmacokinetics

Drug Combinations

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)-coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean +/- SD [% coefficient of variation [CV]) were 7.3 +/- 2.8 (39%), 31.9 +/- 33.6 (106%), and 16.4 +/- 5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2 +/- 1.9 (46%), 8.1 +/- 7.9 (98%), and 1.5 +/- 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein in UGT2B7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB-coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance.

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Title: Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B71c is associated with faster zidovudine clearance and glucuronidation
Creators: Awewura Kwara - Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. akwara@lifespan.org
Margaret Lartey
Isaac Boamah
Naser L Rezk
Joseph Oliver-Commey
Ernest Kenu
Angela D M Kashuba
Michael H Court
Publication Details: Journal of clinical pharmacology, Vol.49(9), pp.1079-1090
Academic Unit: Veterinary Clinical Sciences, Department of
Publisher: England
Grant note: P30 AI042853 / NIAID NIH HHS P30 AI042853-11 / NIAID NIH HHS R01 GM061834-04 / NIGMS NIH HHS P30 AI050410 / NIAID NIH HHS R01GM061834 / NIGMS NIH HHS P30AI042853 / NIAID NIH HHS AI50410 / NIAID NIH HHS K23 AI071760 / NIAID NIH HHS K23 AI071760-03 / NIAID NIH HHS R01 GM061834 / NIGMS NIH HHS
Identifiers: 99900547063501842
Language: English
Resource Type: Journal article