Food consumption, cytochrome P450 3A4 (CYP3A4) presystemic inhibitors, and bioavailability of saquinavir.

It is accepted that the low bioavailability of orally administered saquinavir –SQV– (about 4% for the hard gelatin capsule or tablets –HGCT–, and about 12% for the soft gelatin capsule –SGC– when it is taken with food), is due to an incomplete intestinal absorption and to an extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4) in the gut and liver. As well, P-glycoprotein (P-gp), an efflux pump located on the apical membrane of enterocytes, might contribute to this effect. However, the effect of P-gp on the bioavailability of SQV is contradictory to the results of a recent study of the effect of quercetin (an in vivo inhibitor of P-gp) on the plasma concentrations of SQV, in which coadministration of quercetin to 10 healthy adults did not increase the bioavailability of saquinavir. It is also accepted that simultaneous food ingestion increases the bioavailability and the therapeutic effect of SQV. Recent evidence shows that food increases the bioavailability of SQV by a different mechanism from an effect on gastric pH. Thus, the increase on the plasma concentrations of SQV by food is probably due to that: a) a food-induced augment in SQV solubility; and b) a food-induced raise in the hepatic and portal vein blood flow, which may reduce the first-pass hepatic metabolism effect on bioavailability of SQV. In addition, coadmistration of CYP3A4 intestinal and hepatic inhibitors resulting in an increase of plasma concentrations of SQV. Food consumption and bioavailability of saquinavir. Drugs absorbed into mucosal capillaries of the intestine (e. g. SQV) are delivered to the liver through the hepatic portal vein, so a raise in the hepatic and portal vein blood flow could be associated to a significant increase of the hepatic entry rate, to a decrease of hepatic presystemic clearance, and to an increase of bioavailability of drugs. Therefore, the increase of bioavailability of SQV by food without relation to changes in gastric pH caused by ranitidine is probably due to that food augments SQV solubility and reduces hepatic firs-pass effect on SQV. Cytochrome P450 3A4 (CYP3A4) presystemic inhibitors and bioavailability of saquinavir. Drugs with low oral bioavailability due to effect of CYP3A (e. g. SQV) are very susceptible to presystemic enzymatic inhibition processes, which is reflecting in a markedly increase in their plasma concentrations without changes in the elimination half-life. For instance, ritonavir 100 mg twice a day (a potent inhibitor of CYP3A) when is coadministered with SQV 1,000 mg twice a day results in an increase by 300-800% in SQV area under the concentration-time curve (AUC) compared with SQV without ritonavir. So ritonavir acts as a pharmacokinetic enhancer by inhibiting hepatic and intestinal CYP3A4 isoenzymes. SQV increases in AUC and maximum observed plasma concentration (Cmax) in presence of different inhibitors of CYP3A4 are shown in table I. Moreover, it could be hypothesized that: a) the improvement of bioavailability of SQV, when is coadministered with ranitidine, cimetidine, and omeprazole with ritonavir, is due to a diminish of presystemic clearance associated to the coadministration of these drugs, which may reduce the CYP3A isoenzymes activity and effect on hepatic and intestinal presystemic clearance, although in lesser magnitude than ritonavir; and b) CYP3A enzymes in liver (not in gut-wall) are mainly determinant of low bioavailability of SQV, an assumption that is according to recently published results indicating that the contribution of intestinal CYP3A4 in the low bioavailability of SQV is lower than what has been previously assumed, and the contribution of P-gp is this effect is conflicting. Letters to the Editor 1130-6343/2007/31/1/68 FARMACIA HOSPITALARIA Copyright © 2007 ARÁN EDICIONES, S. L. FARM HOSP Vol. 31. N.° 1, pp. 68-72, 2007