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

This Article Full Text Full Text (PDF) 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 Huisman, M. T. Articles by Schinkel, A. H. Search for Related Content PubMed PubMed Citation Articles by Huisman, M. T. Articles by Schinkel, A. H.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Assessing Safety and Efficacy of Directed P-Glycoprotein Inhibition to Improve the Pharmacokinetic Properties of Saquinavir Coadministered with Ritonavir

Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands (M.T.H., A.H.S.); Cobra Therapeutics Limited, Keele, United Kingdom (J.W.S.); Pharma Development, Roche Products Limited, Welwyn Garden City, United Kingdom (H.R.W.); and Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands (J.H.B.)

Using a mouse model, we tested the effects of in vivo P-glycoprotein inhibition to enhance the oral uptake and penetration into pharmacological sanctuary sites of the human immunodeficiency virus protease inhibitor (HPI) saquinavir. The HPI ritonavir is frequently coadministered with saquinavir to improve saquinavir plasma levels since it strongly reduces the cytochrome P450 3A4-mediated metabolism of saquinavir. Previously, we demonstrated that ritonavir is not an efficient P-glycoprotein inhibitor in vivo, evidenced by the limited oral uptake of saquinavir and its penetration into brain and fetus. Increasing drug concentrations in these sites using more effective P-gp inhibitors might improve therapy but could also lead to toxicity. We orally coadministered ritonavir and saquinavir to mice, with or without the potent P-glycoprotein inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). Upon GF120918 coadministration, two of seven P-glycoprotein-deficient animals died. Using a decreased ritonavir dose, GF120918 coadministration led to a 4.4-fold increase in the saquinavir plasma area under the curve in wild-type mice, whereas no such effect was observed in P-glycoprotein-deficient mice. Despite the decreased ritonavir dose, all mice did suffer from impaired gastric emptying. Including GF120918 in a multiple (bidaily) dosing regimen, we found continued accumulation of saquinavir in brain over several days, resulting in 10-fold higher levels compared with vehicle-treated mice. Transient ritonavir-related neurotoxicity, however, was observed after the fourth and final drug dosing. Clinical attempts to efficiently inhibit P-glycoprotein function for improved HPI disposition may therefore be feasible, but they should be performed without ritonavir and monitored carefully for unexpected toxicities.

Address correspondence to: Dr. A. H. Schinkel, Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: a.schinkel{at}nki.nl

This article has been cited by other articles:

				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. Boffito, D. Maitland, L. Dickinson, D. Back, A. Hill, C. Fletcher, G. Moyle, M. Nelson, B. Gazzard, and A. Pozniak Boosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice daily J. Antimicrob. Chemother., April 1, 2005; 55(4): 542 - 545. [Abstract] [Full Text] [PDF]

				S. Dey, S. Gunda, and A. K. Mitra Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 246 - 255. [Abstract] [Full Text] [PDF]

				K. Ruxrungtham, M. Boyd, S. E. Bellibas, X. Zhang, A. Dorr, S. Kolis, T. Kinchelow, N. Buss, and I. H. Patel Lack of Interaction between Enfuvirtide and Ritonavir or Ritonavir-Boosted Saquinavir in HIV-1-Infected Patients J. Clin. Pharmacol., July 1, 2004; 44(7): 793 - 803. [Abstract] [Full Text] [PDF]

				S. U. C. Sankatsing, J. H. Beijnen, A. H. Schinkel, J. M. A. Lange, and J. M. Prins P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1073 - 1081. [Full Text] [PDF]

				N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]