CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro.

Article Details

Citation

Eagling VA, Wiltshire H, Whitcombe IW, Back DJ

CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro.

Xenobiotica. 2002 Jan;32(1):1-17. doi: 10.1080/00498250110085845.

PubMed ID
11824416 [ View in PubMed
]
Abstract

1. The aim was to identify the major metabolites of saquinavir (SQV) from human hepatic microsomal incubations and the CYP isoform(s) responsible. 2. Ten fractions containing various metabolites were separated by isocratic reversed-phase HPLC and characterized by HPLC, mass spectrometry and NMR. 3. Metabolites were either mono- or di-hydroxylated derivatives of SQV. Fast-atom bombardment and electrospray MS showed that hydroxylation was predominantly situated on the decahydroisoquinoline ring. A major metabolite (M4) was rigorously identified as 6-equatorial-hydroxy SQV. 4. Metabolism of saquinavir to all metabolites was inhibited by the CYP3A4-selective inhibitor ketoconazole (IC50 = 0.55 +/- 0.12 microM). Other isoform-selective inhibitors were non-inhibitory. The protease inhibitors ritonavir, indinavir and nelfinavir potently inhibited SQV metabolism in hepatic microsomes with IC50 = 0.025 +/- 0.004, 0.82 +/- 0.26 and 0. 58 +/- 0.14 microM, respectively. 5. Saquinavir metabolism correlated with immunochemically determined CYP3A4 levels and testosterone 6beta-hydroxylation, but it failed to correlate with either immunochemically determined CYPIA2 levels or marker activities for CYP1A2, 2C9 or 2E1. 6. Heterologously expressed CYP3A4 metabolized saquinavir with a similar metabolic profile to that of human liver microsomes. 7. Km, and Vmax for total SQV metabolism were 0.61 +/- 0.19 microM and 1.82 +/- 1.13 nmol mg(-1) min(-1), respectively. 8. The extensive involvement of hepatic CYP3A4 in the metabolism of saquinavir predicts high intrinsic clearance of saquinavir. Inhibitors of CYP3A4 such as other protease inhibitors will substantially increase the bioavailability of saquinavir.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
SaquinavirCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Amprenavir
Garlic
Garlic can cause a decrease in the absorption of Amprenavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Asunaprevir
Garlic
Garlic can cause a decrease in the absorption of Asunaprevir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Atazanavir
Garlic
Garlic can cause a decrease in the absorption of Atazanavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Darunavir
Garlic
Garlic can cause a decrease in the absorption of Darunavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Fosamprenavir
Garlic
Garlic can cause a decrease in the absorption of Fosamprenavir resulting in a reduced serum concentration and potentially a decrease in efficacy.