Dose‐dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL

Abstract

Aims Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P-glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose-dependently in vivo by cremophor EL, an 'inactive' pharmaceutic aid known to inhibit PGP in vitro. Methods In a randomized, placebo-controlled, double-blind, four phase cross-over design single doses of oral saquinavir (Invirase 1 , 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (C max ), time to reach C max (t max ) and terminal elimination half-life (t 1/2 ). Results Cremophor EL dose-dependently increased C max , AUC(0,4 h), and AUC(0,?) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13-fold for both C max and AUC(0,4 h) and 5-fold for AUC(0,?). The terminal half-life and the time to reach C max (t max ) were unchanged. Conclusions Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…In in vitro experiments, polysorbate 80 was able to inhibit P-gp activity and to increase daunorubicin intracellular levels in cell cultures [112]. Polyoxyl castor oil and polysorbate 80 (substances used in drug formulations to dissolve some lipophylic and/or poorly soluble drugs, especially paclitaxel and docetaxel) were reported to increase the oral absorption of saquinavir and digoxin, respectively, through interaction with P-gp activity [113,114].…”

A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

“…Intestinal Pgp has been shown to significantly reduce intestinal uptake of saquinavir in-vitro (Alsenz et al 1998;Williams & Sinko 1999) and coadministration of the selective Pgp inhibitor GF120918 resulted in significant increases in saquinavir plasma concentrations in mice (Huisman et al 2003). Martin-Facklam et al (2002) proposed that the dose-dependent increase in saquinavir bioavailability observed following co-administration of cremophor was mediated by a Pgp-mediated effect. However, at a molecular level, the comparative effects of surfactants, such as cremophor and TPGS, on intestinal cells and Pgp-functionality is far from clear, with evidence reported of diverse functionality between surfactants on cell surface membranes or transporters (Rege et al 2001;Bogman et al 2003;Cornaire et al 2004).…”

Improvement of the Oral Drug Absorption of Topotecan through the Inhibition of Intestinal Xenobiotic Efflux Transporter, Breast Cancer Resistance Protein, by Excipients

“…Lo (2003) reported that Tween 20 markedly enhanced the intracellular accumulation of epirubicin in Caco-2 cells and enhanced mucosal-to-serosal absorption of epirubicin in the rat jejunum and ileum. Previous reports suggest that coadministration of excipients enhanced oral absorption of P-gp substrates not only because of improved solubilization of drugs, but also inhibition of P-gp-mediated efflux (Yu et al, 1999;Martin-Facklam et al, 2002;Varma and Panchagnula, 2005). These excipients are commonly used in human pharmaceutical formulations and are considered safe and relatively nontoxic.…”