Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model

Shibata, Nobuhito; Gao, Weihua; Okamoto, Hiroyuki; Kishida, Tomoyuki; Iwasaki, Koji; Yoshikawa, Yukako; Takada, Kanji

doi:10.1002/jps.10051

Cited by 25 publications

(14 citation statements)

References 25 publications

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“…Despite anatomical differences between humans and rats, the oral bioavailability of SQV in the two species is similar, both low (4%) and variable (Roche Laboratories, 2001;Shibata et al, 2002). Perhaps this similarity is due to the structural and functional similarity between rodent Mdr1, Mrp2, and CYP3A and their human counterparts (i.e., MDR1, MRP2, and CYP3A4) (Schinkel, 1997b;König et al, 1999;Bogaards et al, 2000), thus making the rat a relevant model for investigating SQV oral bioavailability in humans.…”

Section: Usansky Et Almentioning

confidence: 99%

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Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Usansky¹,

Hu²,

Sinko³

2008

Drug Metabolism and Disposition

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ABSTRACT:The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir ( -(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F a ‫؍‬ 0.07%) and in vivo [C max ‫؍‬ 0.068 g/ml; area under the curve (AUC) ‫؍‬ 6.8 g ⅐ min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation ‫؍‬ 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2-to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapylimiting drug-drug transporter and enzyme interactions.

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Section: Usansky Et Almentioning

confidence: 99%

“…The parameters were determined based on the concentrations of metabolites equivalent to SQV; n ϭ 3 to 7 rats/group. (Shibata et al, 2002). Moderate amounts of metabolites (1 Ϫ F gut ϭ ϳ20%) seen in the mesenteric and portal circulation indicate that SQV intestinal metabolism is a not significant factor in its low oral bioavailability.…”

Section: Usansky Et Almentioning

confidence: 99%

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Usansky¹,

Hu²,

Sinko³

2008

Drug Metabolism and Disposition

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“…SQV and NFV, the most effective PIs in attenuating neutrophil functions, caused a significant inhibition of apoptosis, while APV had only small effects on neutrophil functions and on neutrophil apoptosis. The concentrations of the PIs used in this study are readily achievable with oral dosing regimens in humans (46,51). The PIs act by blocking the HIV aspartyl protease, a viral enzyme that cleaves the HIV Gag and Gag-Pol polyprotein backbone, thereby interrupting the viral life cycle.…”

Section: Discussionmentioning

confidence: 99%

Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Hadad

Lévy

Schlaeffer

et al. 2007

Clin Vaccine Immunol

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Impairment of neutrophil functions and high levels of apoptotic neutrophils have been reported in human immunodeficiency virus (HIV) patients. The aim of the present study was to investigate the direct in vitro effects of the different HIV protease inhibitors (PIs) on neutrophil functions and apoptosis and to explore their mechanisms of action. The effects of nelfinavir (NFV), saquinavir (SQV), lopinavir (LPV), ritonavir (RTV), and amprenavir (APV) in the range of 5 to 100 g/ml on neutrophil function, apoptosis, and -calpain activity were studied. The neutrophil functions studied included superoxide production stimulated by 5 ng/ml phorbol myristate acetate, 5 ؋ 10 ؊7 M N-formyl-methionyl-leucyl-phenylalanine, and 1 mg/ml opsonized zymosan; specific chemotaxis; random migration; and phagocytosis. Apoptosis was determined by DNA fragmentation, fluorescein isothiocyanate-annexin V binding, and nuclear morphology. All three neutrophil functions, as well as apoptosis, were similarly affected by the PIs. SQV and NFV caused marked inhibition and LPV and RTV caused moderate inhibition, while APV had a minor effect. -Calpain activity was not affected by the PIs in neutrophil lysate but was inhibited after its translocation to the membranes after cell stimulation. SQV, which was the most potent inhibitor of neutrophil functions and apoptosis, caused significant inhibition of calpain activity, while APV had no effect. The similar patterns of inhibition of neutrophil functions and apoptosis by the PIs, which coincided with inhibition of calpain activity, suggest the involvement of calpain activity in the regulation of these processes.

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“…31,32) In our previous studies on pharmacokinetic interactions among the HIV PIs currently used in clinical therapy, we observed that IDV inhibited the metabolism of APV, NFV and SQV with K i values of 0.67, 2.76 and 3.55 mM, respectively. [10][11][12][13] After oral administration of APV, SQV or NFV with IDV, their AUC values in the presence of IDV were increased 1.6-, 9.5-and 2.3-fold, respectively, compared with any of them alone. On the other hand, the AUC values of APV, SQV and NFV after intravenous co-administration with IDV increased by 1.4-, 1.2-and 1.5-fold, respectively, and showed no notable increase compared to those obtained from oral administration.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] According to the previous studies, the degrees of in vivo pharmacokinetic interaction between any combination of two drugs selected out of the above five were highly variable. [10][11][12] Even though IDV had the strongest inhibitory effect on APV metabolism in rat liver microsomes, the in vivo effects of an HIV PI after co-administration with IDV could not always be predicted from in vitro results, suggesting the presence of another interaction process besides metabolism in the liver. 13) It has been suggested that in some drugs the role of intestinal metabolism is greater than that of hepatic metabolism in the overall first-pass effect.…”

mentioning

confidence: 97%

Effect of Indinavir on the Intestinal Exsorption of Amprenavir, Saquinavir and Nelfinavir after Intravenous Administration in Rats.

Gao

Kageyama

Inoue

et al. 2003

Biological & Pharmaceutical Bulletin

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Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model

Cited by 25 publications

References 25 publications

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Effect of Indinavir on the Intestinal Exsorption of Amprenavir, Saquinavir and Nelfinavir after Intravenous Administration in Rats.

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