The effect of atazanavir and atazanavir/ritonavir on UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe.
Atazanavir (ATV) is known to inhibit UGT1A1-mediated glucuronidation. Here we report the effect of ATV and ATV/ritonavir (RTV) on another UGT1A isoenzyme, UGT1A4. Twenty-one healthy volunteers received a single dose of 100 mg of oral lamotrigine on days 1, 13, and 27; on each occasion blood was sampled before the dose was administered and through 120 h after ingestion of the drug. On days 8-17 the subjects received oral ATV 400 mg q.d. On days 18-30 the subjects received oral ATV 300 mg plus oral RTV 100 mg q.d. Seventeen subjects were evaluable for pharmacokinetic analysis. Geometric mean ratios (+90% confidence intervals (CIs)) of lamotrigine area under the plasma concentration-time curve (AUC)(0-inf) and peak plasma concentration (C(max)) for ATV + lamotrigine and for lamotrigine alone were 0.88 (0.86-0.91) and 0.99 (0.95-1.02), respectively; the corresponding ratios for ATV/RTV and for lamotrigine were 0.68 (0.65-0.70) and 0.94 (0.90-0.97), respectively. The mean ratio of lamotrigine-2N-glucuronide to lamotrigine AUC(0-inf) increased from 0.45 for lamotrigine to 0.71 for ATV/RTV + lamotrigine. ATV alone does not significantly influence glucuronidation of lamotrigine. In contrast, ATV/RTV results in moderately decreased exposure to lamotrigine.
Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. D.Burger@akf.umcn.nl
D M
DM
Burger
A
A
Huisman
N
N
Van Ewijk
H
H
Neisingh
P
P
Van Uden
G A
GA
Rongen
P
P
Koopmans
R J
RJ
Bertz
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D014453:Glucuronosyltransferase / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D015336:Molecular Probe Techniques; D009842:Oligopeptides / Q000494:pharmacology*; D010641:Phenotype; D011446:Prospective Studies; D011725:Pyridines / Q000494:pharmacology*; D012016:Reference Values; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012680:Sensitivity and Specificity; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D019380:Anti-HIV Agents; D009842:Oligopeptides; D011725:Pyridines; D014227:Triazines; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase; D019438:Ritonavir; D000077213:Lamotrigine