Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man

Abstract

Aims: Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.

Methods: After an overnight fast, eight healthy volunteers were treated with either 400 ml grapefruit juice or water before intravenous (12 mg) or oral saquinavir (600 mg) was administered. Serial blood samples were obtained over the following 24 h and standardized meals were served 5 and 10 h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.

Results: The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76+/-96 (water, mean (s.d.) to 114+/-70 (microg l[-1] h) (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.

Conclusions: The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.

Figure 1

Plasma concentration-time curves of a) intravenous or b) oral saquinavir after pretreatment with water (—) or grapefruit juice (– – –): Intravenous (12 mg) or oral saquinavir (600 mg) was administered to eight healthy volunteers treated with water or grapefruit juice. Treatment with grapefruit juice does not affect the kinetics of saquinavir after intravenous administration, but leads to a significant increase in the area under the curve after oral ingestion of saquinavir. The second peak in the oral plasma concentration-time curves is associated with the lunch served at 5 h.

Figure 2

Total body clearance and bioavailability of saquinavir after pretreatment with water or grapefruit juice. While the clearance of saquinavir was not significantly affected by grapefruit juice, its bioavailability showed a significant increase.