Premium
Interindividual Variability in Pharmacokinetics of Generic Nucleoside Reverse Transcriptase Inhibitors in TB/HIV‐Coinfected Ghanaian Patients: UGT2B7 *1c Is Associated With Faster Zidovudine Clearance and Glucuronidation
Author(s) -
Kwara Awewura,
Lartey Margaret,
Boamah Isaac,
Rezk Naser L.,
OliverCommey Joseph,
Kenu Ernest,
Kashuba Angela D. M.,
Court Michael H.
Publication year - 2009
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009338482
Subject(s) - zidovudine , stavudine , pharmacokinetics , glucuronidation , lamivudine , ugt2b7 , reverse transcriptase inhibitor , pharmacology , virology , chemistry , medicine , human immunodeficiency virus (hiv) , sida , virus , viral disease , hepatitis b virus , microsome , enzyme , biochemistry
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 UGT2B 7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB‐coinfected Ghanaians are similar to other populations, whereas the UGT2B 7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance