Docosahexaenoic acid (DHA) inhibits saquinavir metabolism in-vitro and enhances its bioavailability in rats

This study investigated the effect of docosahexaenoic acid (DHA) on the metabolism of saquinavir by cytochrome P450 3A (CYP3A) in‐vitro using rat liver microsomes and in‐vivo using rats. DHA showed a concentration‐dependent inhibition of in‐vitro saquinavir metabolism with Km, Vmax and Ki values of 2.21 μM, 0.054 μmol h−1 (mg protein)−1 and 149.6 μM, respectively. After oral co‐administration with 250 μg kg−1 DHA, the bioavailability of saquinavir significantly increased approximately 4 fold (P < 0.01) without affecting the elimination half‐life, as compared with the control. In contrast, oral administration of DHA did not affect the kinetic parameters of saquinavir administered intravenously. These results suggest that the inhibitory effect of DHA on saquinavir metabolism predominantly takes place in the gut and imply that DHA impairs the function of enteric, but not of hepatic, CYP3A. The pharmacokinetic interaction occurred only when DHA was taken simultaneously with oral administration of saquinavir. These results considered together with the lack of time‐dependent saquinavir metabolism inactivation effects in‐vitro, imply that the inhibitory effect of DHA is primarily reversible. It is concluded that DHA inhibited saquinavir metabolism in‐vitro and enhanced the oral bioavailability of saquinavir in rats.