Metabolism of amprenavir in liver microsomes: Role of CYP3A4 inhibition for drug interactions

被引:94
作者
Decker, CJ [1 ]
Laitinen, LM [1 ]
Bridson, GW [1 ]
Raybuck, SA [1 ]
Tung, RD [1 ]
Chaturvedi, PR [1 ]
机构
[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA
关键词
D O I
10.1021/js980029p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Amprenavir (141W94, VX-478, KVX-478) is metabolized primarily by CYP3A4 (cytochrome P450 3A4) in recombinant systems and human liver microsomes (HLM). The effects of ketoconazole, terfenadine, astemizole, rifampicin, methadone, and rifabutin upon amprenavir metabolism were examined in vitro using HLM. Ketoconazole, terfenadine, and astemizole were observed to inhibit amprenavir depletion, consistent with their known specificity for CYP3A4. The HIV protease inhibitors, indinavir, saquinavir, ritonavir, and nelfinavir, were included in incubations containing amprenavir to examine the interactions of HIV protease inhibitors in vitro. The order of amprenavir metabolism inhibition in human liver microsomes was observed to be: ritonavir > indinavir > nelfinavir > saquinavir. The K-i value for amprenavir-mediated inhibition of testosterone hydroxylation in human liver microsomes was found to be approximately 0.5 mu M. Studies suggest that amprenavir inhibits CYP3A4 to a greater extent than saquinavir, and to a much lesser extent than ritonavir. Amprenavir, nelfinavir, and indinavir appear to inhibit CYP3A4 to a moderate extent, suggesting a selected number of coadministration restrictions.
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页码:803 / 807
页数:5
相关论文
共 27 条
  • [1] *ABB LAB, 1996, NORV RIT PROD INF
  • [2] Protease inhibitors in patients with HIV disease - Clinically important pharmacokinetic considerations
    Barry, M
    Gibbons, S
    Back, D
    Mulcahy, F
    [J]. CLINICAL PHARMACOKINETICS, 1997, 32 (03) : 194 - 209
  • [3] BATISSE D, 1997, P INT C ANT AG CHEM, pI206
  • [4] BATTEGAY M, 1997, P INT C ANT AG CHEM, P203
  • [5] CAMERON G, 1996, 3 C RETR OPP INF WAS
  • [6] Chiba M, 1996, DRUG METAB DISPOS, V24, P307
  • [7] DEEKS S, 1997, P INT C ANT AG CHEM, pI205
  • [8] Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir
    Eagling, VA
    Back, DJ
    Barry, MG
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1997, 44 (02) : 190 - 194
  • [9] FARRAR G, 1994, P BPS, V12, pP162
  • [10] FAUCI AS, 1996, FED REGIST, V61