RT Journal Article
SR Electronic
T1 Intestinal Metabolism Promotes Regional Differences in Apical Uptake of Indinavir: Coupled Effect of P-Glycoprotein and Cytochrome P450 3A on Indinavir Membrane Permeability in Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 586
OP 593
DO 10.1124/jpet.301.2.586
VO 301
IS 2
A1 Lilian Y. Li
A1 Gordon L. Amidon
A1 Jae Seung Kim
A1 Tycho Heimbach
A1 Filippos Kesisoglou
A1 John T. Topliss
A1 David Fleisher
YR 2002
UL http://jpet.aspetjournals.org/content/301/2/586.abstract
AB The purpose of this study was to investigate transport and metabolism contributions to low indinavir permeability in rat ileum and enhanced drug permeability in the jejunum. Permeability models utilized included single pass in situ rat intestinal perfusion and rat intestinal tissue mounted in Ussing chambers. Intestinal metabolism was measured by fractional appearance of metabolite (Fmet), determined as the percentage of the predominant metabolite M6 over luminal loss of indinavir in the perfusion model. Among the results, indinavir exhibited bidirectional transport across rat ileum. Verapamil and cyclosporin A inhibited net flux by 37 and 38%, respectively. Intestinal metabolism of indinavir was most significant in upper jejunum (Fmet = 65.78 ± 19.02%), decreasing in midjejunum (Fmet = 31.58 ± 5.63%). M6 was not detectable in ileum or colon. Western blot analysis of rat intestinal mucosal tissue samples confirmed that the axial expression of CYP3A was consistent with the regional pattern of formation of M6. Intestinal metabolism was saturable and could be inhibited by the CYP3A inhibitor, ketoconazole. A low luminal concentration of indinavir (1 μM) was associated with highFmet (87.90 ± 14.30%), whereas a high luminal concentration of indinavir (50 μM) was associated with lowFmet (35.84 ± 11.59%). In the presence of ketoconazole, both Fmet and permeability of indinavir were reduced in the jejunum. These results suggest that 1) intracellular metabolism of indinavir enhances apical uptake of indinavir in the rat jejunum as a function of the increased concentration gradient generated across the epithelial cell membrane and 2) the efflux transporter P-glycoprotein limits apical uptake of indinavir in the ileum, resulting in low apparent permeability. The American Society for Pharmacology and Experimental Therapeutics