QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.056390v1 308/3/941    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mouly, S. J. Articles by Watkins, P. B. Search for Related Content PubMed PubMed Citation Articles by Mouly, S. J. Articles by Watkins, P. B.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Contributions of CYP3A4, P-glycoprotein, and Serum Protein Binding to the Intestinal First-Pass Extraction of Saquinavir

General Clinical Research Center (S.J.M., P.B.W.), Division of Pharmacotherapy (M.F.P., P.B.W.), and Department of Medicine (P.B.W.), University of North Carolina, Chapel Hill, North Carolina

Using CYP3A4-expressing Caco-2 cell monolayers, we assessed the roles of CYP3A4-mediated metabolism, P-glycoprotein (P-gp)-mediated efflux, and serum protein binding in determining the extent of the intestinal first-pass extraction (E_i) of saquinavir. Saquinavir (5–40 µM) was added to the apical compartment of culture inserts. After 3 h, apical and basolateral media and cell scrapings were analyzed for saquinavir and a major CYP3A4-mediated metabolite (M7). The intracellular concentration of saquinavir was estimated from the degree of inhibition of CYP3A4 catalytic activity (midazolam 1'-hydroxylation). Compared with vehicle, the P-gp inhibitor LY335979 (zosuquidar trihydrochloride) (0.5 µM, apical) increased saquinavir cell content and M7 formation rate, but decreased the E_i by 50% due to a >90% increase in the amount of saquinavir recovered in the basolateral compartment. Compared with LY335779, physiological concentrations of basolateral serum proteins [human serum albumin and 1-acid glycoprotein (AAG)] increased saquinavir permeability by a similar degree but decreased the E_i by 50% due to a marked reduction in M7 formation. Increasing AAG concentration (1.0–2.5 g/l) had no additional effect on permeability or E_i. An estimate of the range of the E_i of saquinavir (7–60%) was less than has been predicted based on in vitro data (>99%) but was consistent with a clinical study involving grapefruit juice. The incidental finding of greater M7 formation after basolateral compared with apical dosing could not be explained by differences in saquinavir cell content. We conclude that variable intestinal first-pass extraction of saquinavir in human immunodeficiency virus-infected patients could reflect variation in P-gp-mediated efflux and/or CYP3A4-catalyzed metabolism, but not in blood AAG levels.

Address correspondence to: Dr. Paul B. Watkins, General Clinical Research Center, Room 3005 Bldg. APCF, CB# 7600, University of North Carolina Hospitals, Chapel Hill, NC 27599-7600. E-mail: pbwatkins{at}med.unc.edu

This article has been cited by other articles:

				N. Ngo, Z. Yan, T. N. Graf, D. R. Carrizosa, A. D. M. Kashuba, E. C. Dees, N. H. Oberlies, and M. F. Paine Identification of a Cranberry Juice Product that Inhibits Enteric CYP3A-Mediated First-Pass Metabolism in Humans Drug Metab. Dispos., March 1, 2009; 37(3): 514 - 522. [Abstract] [Full Text] [PDF]

				M. F Paine, W. W Widmer, S. N Pusek, K. L Beavers, A. B Criss, J. Snyder, and P. B Watkins Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine Am. J. Clinical Nutrition, April 1, 2008; 87(4): 863 - 871. [Abstract] [Full Text] [PDF]

				L. W. Chinn, J. M. Gow, M. M. Tse, S. L. Becker, and D. L. Kroetz Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein J. Antimicrob. Chemother., July 1, 2007; 60(1): 61 - 67. [Abstract] [Full Text] [PDF]

				A. Marin-Niebla, L. F. Lopez-Cortes, R. Ruiz-Valderas, P. Viciana, R. Mata, A. Gutierrez, R. Pascual, and M. Rodriguez Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients Antimicrob. Agents Chemother., June 1, 2007; 51(6): 2035 - 2042. [Abstract] [Full Text] [PDF]

				N. von Hentig, A. Muller, C. Rottmann, T. Wolf, T. Lutz, S. Klauke, M. Kurowski, B. Oertel, B. Dauer, S. Harder, et al. Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen Antimicrob. Agents Chemother., April 1, 2007; 51(4): 1431 - 1439. [Abstract] [Full Text] [PDF]

				M. F Paine, W. W Widmer, H. L Hart, S. N Pusek, K. L Beavers, A. B Criss, S. S Brown, B. F Thomas, and P. B Watkins A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1097 - 1105. [Abstract] [Full Text] [PDF]

				M. F. Paine, A. B. Criss, and P. B. Watkins Two Major Grapefruit Juice Components Differ in Time to Onset of Intestinal CYP3A4 Inhibition J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1151 - 1160. [Abstract] [Full Text] [PDF]