An examination of the effect of intestinal first pass extraction on intestinal lymphatic transport of saquinavir in the rat.
OBJECTIVE
To assess the impact of intestinally based efflux/elimination processes on the extent of intestinal lymphatic transport of saquinavir. To compare the relative effects of co-administration of P-gp/CYP modulators on intestinal lymphatic transport versus systemic bioavailability of saquinavir.


METHODS
A cremophor mixed micelle formulation of saquinavir alone, or co-administered with P-gp/CYP modulators, verapamil, ketoconazole or cyclosporine, was dosed intraduodenally in the mesenteric lymph duct cannulated anaesthetized rat model.


RESULTS
Co-administration of P-gp/CYP modulators resulted in significant increases in the extent of intestinal lymphatic transport of saquinavir. A comparison of the relative enhancement of lymphatic transport and plasma bioavailability compared to control (i.e. saquinavir alone) reveals a greater effect of verapamil and ketoconazole on the amount of drug transported by the lymphatic route, an observation consistent with a preferential targeting of saquinavir via the intestinal lymphatics. In contrast co-administration of cyclosporine increased both the extent of lymphatic transport (5.5-fold), and systemic bioavailability (4.1-fold).


CONCLUSIONS
Intestinal P-gp/CYP efflux/elimination restricts saquinavir transport via the intestinal lymphatics in the rat. Targeted increases in intestinal lymphatic levels of saquinavir may be achieved by selective inhibition of intestinal P-gp and/or CYP.
Griffin
Brendan T
BT
School of Pharmacy, University College Cork, Cork, Ireland. brendan.griffin@ucc.ie
O'Driscoll
Caitriona M
CM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001693:Biological Transport, Active; D016572:Cyclosporine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003627:Data Interpretation, Statistical; D007408:Intestinal Absorption / Q000502:physiology*; D007654:Ketoconazole / Q000494:pharmacology; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008823:Micelles; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics*; D014280:Triglycerides / Q000378:metabolism; D014304:Triolein / Q000737:chemistry; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D008823:Micelles; D014280:Triglycerides; D014304:Triolein; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D014700:Verapamil; D019258:Saquinavir; D007654:Ketoconazole