TY - JOUR
T1 - Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected ghanaian patients
T2 - UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation
AU - Kwara, Awewura
AU - Lartey, Margaret
AU - Boamah, Isaac
AU - Rezk, Naser L.
AU - Oliver-Commey, Joseph
AU - Kenu, Ernest
AU - Kashuba, Angela D.M.
AU - Court, Michael H.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - Interindividual variability
KW - NRTIs
KW - Pharmacokinetics
KW - Rifampin
KW - UGT2B7
UR - http://www.scopus.com/inward/record.url?scp=69549103001&partnerID=8YFLogxK
U2 - 10.1177/0091270009338482
DO - 10.1177/0091270009338482
M3 - Article
C2 - 19628728
AN - SCOPUS:69549103001
SN - 0091-2700
VL - 49
SP - 1079
EP - 1090
JO - Journal of Clinical Pharmacology
JF - Journal of Clinical Pharmacology
IS - 9
ER -