OMARA EM, MUMMANENI V, BURCHELL B, RANDALL D, GERALDES M; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 334.
Bristol-Myers Squibb Pharmaceutical Res. Inst., Princeton, NJ
BACKGROUND: BMS-232632 (BMS) is a new protease inhibitor (PI) that has shown excellent anti-HIV activity. Saquinavir soft gel (SQV-SG) was evaluated as a companion to BMS for dual PI therapy. Reversible elevations of total bilirubin (TB) to >20micro-M {=1.2 mg/dl} were noted in 95% of subjects when BMS was added to saquinavir. The UDP-GT 1A1 enzyme catalyzes bilirubin conjugation; enzyme production is modulated by two promoter region alleles, 6 and 7. In vitro, BMS was observed to competitively inhibit UDP-GT 1A1 isoform, a relationship was sought between subjects UDP-GT 1A1 genotype and observed total bilirubin elevations.METHODS: 20 of 24 subjects receiving BMS+SQV-SG were genotyped for alleles 6 and 7 by the method of Burchell. Direct and total bilirubin values were determined by auto-analyzer and indirect bilirubin calculated. A total bilirubin elevation >43 micro-M (2.5 mg/dl) was selected as jaundice could be observed at and above that level.RESULTS: Descriptive statistics for total bilirubin (values in micro-M) by genotype [table: see text]. Using a 2x2 bilirubin ( 43micro-M) vs. genotype contingency table, the odds of a total bilirubin elevation >43 micro-M were estimated to be 5.6 times higher for subjects with genotype 6/7 or 7/7 than for genotype 6/6. The risk (for subjects with genotype 6/7 or 7/7 relative to genotype 6/6) of a total bilirubin elevation >43 micro-M was estimated to be 3.1.CONCLUSIONS: Presence of at least one 7 allele seems to be associated with higher odds of a total bilirubin elevation >43micro-M (2.5 mg/dl) during BMS-232632 administration.KEYWORDS: Bilirubin; BMS-232632; Genotype
Publication Types:
Keywords:
- Alleles
- Bilirubin
- DNA Primers
- Genotype
- Glucuronosyltransferase
- In Vitro
- Jaundice
- Jaundice, Neonatal
- Promoter Regions (Genetics)
- Pyridines
- Saquinavir
- Uridine Diphosphate
- atazanavir
- genetics
Other ID:
UI: 102247118
From Meeting Abstracts