The effect of atazanavir and atazanavir/ritonavir on UDP-glucuronosyltransferase using lamotrigine as a phenotypic probe

• Published in: Clinical pharmacology and therapeutics Vol. 84; no. 6; p. 698
• Main Authors: Burger, D M, Huisman, A, Van Ewijk, N, Neisingh, H, Van Uden, P, Rongen, G A, Koopmans, P, Bertz, R J
• Format: Journal Article
• Language: English
• Published: United States 01.12.2008
• Subjects: Administration, Oral; Adult; Anti-HIV Agents - pharmacology; Atazanavir Sulfate; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Glucuronosyltransferase - drug effects; Glucuronosyltransferase - metabolism; Humans; Male; Middle Aged; Molecular Probe Techniques; Oligopeptides - pharmacology; Phenotype; Prospective Studies; Pyridines - pharmacology; Reference Values; Ritonavir - administration & dosage; Ritonavir - pharmacokinetics; Sensitivity and Specificity; Triazines - administration & dosage; Triazines - pharmacokinetics; Young Adult
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2008.106

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.