Pharmacokinetic interactions between HIV-protease inhibitors in rats

The interactions of four HIV-protease inhibitors, ritonavir (RIT), saquinavir (SAQ), indinavir (IND) and nelfinavir (NEL), were examined by in vitro metabolic studies using rat liver microsomal fractions. The substrate concentrations employed were 0.75 similar to 12 mu M, and the inhibitor concentrations were 2.5 similar to 60 mu M. The metabolic clearance rates of SAQ, NEL and IND as determined by V-max/K-m were 170.9 +/- 10.9, 126.0 +/- 4.4 and 73.0 +/- 2.0 mu L/min/mg protein, respectively. RIT was a potent inhibitor of the other three protease inhibitors, and the inhibition constants (K-i) were 1.64 mu M for SAQ 0.95 mu M for IND and 1.01 mu M for NEL. NEL was the second strongest inhibitor with a K-i for NEL inhibition of IND metabolism of 2.14 mu M. IND was the third strongest inhibitor with K(i)s of 2.76 mu M for inhibition of NEL and 3.55 mu M for inhibition of SAQ. As SAa has the highest metabolic clearance rate, the K-i for the SAQ inhibition of IND metabolism was high, 9.50 mu M. Based on these in vitro results, drug interactions between NEL and IND or RIT were studied after oral administration to rats where the dose of each drug was 20 mg/kg. The C-max and AUC of NEL were increased 3.6- and 8.5-fold by the co-administration with RIT. However, in contrast to co-administration of NEL and RIT, the effect of IND on the pharmacokinetics of NEL was negligible and the t(1/2) of NEL was not significantly increased by IND. Therefore, the combination of NEL and IND is recommended as a combination therapy for AIDS patients. Copyright (C) 1999 John Wiley & Sons, Ltd.