In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats.
The drug interactions between a new human immune deficiency virus (HIV) protease inhibitor, amprenavir, and four other protease inhibitors which are presently used have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration studies. The metabolic clearance rates (Vmax/Km) of amprenavir, saquinavir, indinavir and nelfinavir in rat liver microsomes were 50.67+/- 3.77, 170.88 +/- 15.34, 73.01 +/- 2.76 and 126.06 +/- 6.23 microLmin(-1) (mg protein)(-1), respectively, and the degree of metabolicclearance was in the order of saquinavir > nelfinavir > indinavir > amprenavir > ritonavir. The inhibition constants (Ki) of ritonavir for amprenavir, indinavir, nelfinavir and saquinavir were 2.29, 0.95, 1.01 and 1.64 microM, respectively, and that of indinavir for amprenavir was 0.67, indicating that amprenavir metabolism in rat liver microsomes was strongly inhibited by indinavir. The Ki values of amprenavir for indinavir, nelfinavir and saquinavir were 7.41, 2.13 and 16.11 microM, respectively, and those of nelfinavirand saquinavirforamprenavirwere 9.15 and 34.57 microM, respectively. The area under the concentration vs time curve (AUC) of amprenavir after oral co-administration with saquinavir, indinavir, nelfinavir or ritonavir (20 mg kg(-1) for each oral dose in rats) was increased by 1.6-, 2.0-, 1.2- and 9.1-fold, respectively. The AUC values of saquinavir, indinavir and nelfinavir by co-administration with amprenavir showed about 7.3-, 1.3-, and 7.9-fold increase, respectively. These observations suggested that the oral bioavailability of amprenavir was not so affected by co-administration with saquinavir, nelfinavir or indinavir, compared with ritonavir, whereas amprenavir markedly affected the oral bioavailability of saquinavir and nelfinavir. In addition, the in-vivo effects after co-administration of two kinds of HIV protease inhibitors cannot always be predicted from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. However, these results provide useful information for the treatment of AIDS patients when they receive a combination therapy with two kinds of HIV protease inhibitor.
Shibata
Nobuhito
N
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan. shibata@mb.kyoto-phu.ac.jp
Gao
Weihua
W
Okamoto
Hiroyuki
H
Kishida
Tomoyuki
T
Yoshikawa
Yukako
Y
Takada
Kanji
K
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002219:Carbamates; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005663:Furans; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D019469:Indinavir / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir