Hepatic and intestinal contributions to pharmacokinetic interaction of indinavir with amprenavir, nelfinavir and saquinavir in rats.
To elucidate the aspects of pharmacokinetic interactions among HIV protease inhibitors (PIs), we investigated the effects of indinavir (IDV) on the hepatic and intestinal first-pass metabolism of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV), in rats. After oral co-administration with IDV, the area under the concentration versus time curves (AUC) of APV, SQV and NFV increased significantly by 1.6-, 9.5- and 2.3-fold, respectively, compared with mono-administration. After intravenous administration, the AUC of APV, SQV and NFV also increased in the presence of IDV by 1.4-, 1.2- and 1.5-fold, respectively. Mean concentrations of APV, SQV and NFV in the liver extracellular fluid, measured using a liver microdialysis method, were very low compared with their Michaelis constants regardless of co-administration of IDV, suggesting that APV, SQV and NFV metabolism follows linear kinetics in the liver. This finding also indicates that metabolism of PIs depended on the metabolic clearance rate in the liver microsomes. The oral bioavailability of SQV in the presence of IDV increased markedly by 8.5-fold, and that of APV and NFV also increased by 1.2- and 1.5-fold, respectively. On the basis of the well-stirred model, the hepatic availabilities of APV, SQV and NFV in the presence of IDV increased by 1.1-, 1.4- and 1.5-fold, and the intestinal availabilities increased by 1.1-, 6.2- and 1.1-fold, respectively. These results suggest that both hepatic and intestinal metabolism were essentially involved in the interactions between IDV and other HIV PIs, and the degree of those contributions varied with each combination of HIV PIs.
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
Weihua
W
Gao
Tomoyuki
T
Kishida
Michiharu
M
Kageyama
Keisuke
K
Kimura
Yukako
Y
Yoshikawa
Nobuhito
N
Shibata
Kanji
K
Takada
D000818:Animals; D019540:Area Under Curve; D002219:Carbamates; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005663:Furans; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D019888:Nelfinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir