Protease inhibitor saquinavir

Jones K, Hoggard PC, Khoo S, Maher B, Back DJ (2001) Effect of alphal-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro, Br J Chn Pharmacol 51 99-102... 

Fitzsimmons, M. E., Collins, J. M., Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4 potential contribution to high first-pass metabolism, Drug. Metab. Dispos. 1997, 25, 256-266. 

Some P-gp inhibitors have been tested in clinical trials (e.g., GF120918, PSC 833) [88, 89], Shortly before birth, it is often desirable to expose the fetus to anti-HIV medications to prevent HIV transmission from the mother to the fetus during delivery. Preperfusion with P-gp inhibitors increased fetal penetration of the protease inhibitor saquinavir in in vitro placental models, and it has been hypothesized that P-gp may be responsible for limiting fetal exposure to HIV protease inhibitors, methadone, anthracyclines, and taxanes [90-93],... 

Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krahenbuhl S. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol 1998 45(4) 355-359. 

Eagling VA, Profit L, Back DJ. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol 1999 48(4) 543-552. 

Jacobsen H, Brun-Vezinet F, Duncan I, Hanggi M, Ott M, Vella S, Weber J, Mous J. Genotypic. characterization of HIV-1 from patients after prolonged treatment with protease inhibitor saquinavir. In Abstracts of the 3rd International Workshop on HIV Drug Resistance. London MediTech Media, 1994 16. 

Grapefruit juice has also been shown to inhibit CYP3A4 and P-gp in the small intestine, and hence, can elevate the oral bioavailability of lipophilic drugs [98,99]. Concomitant intake of grapefruit juice with the lipophilic cholesterol-lowering medication simvastatin caused a 16-fold increase in the AUC of simvastatin [100]. The oral bioavailability of the lipophilic HIV protease inhibitor saquinavir was doubled following concomitant administration with grapefruit juice [101]. 

Rouquayrol, M., Gaucher, B., Roche, D., et al. Transepithelial transport of prodrugs of the HIV protease inhibitors saquinavir, indinavir, and nelfinair across Caco-2 cell monolayers. Pharm. Res. 19 1704-1712, 2002. 

The findings of this study were consistent with the surrogate marker studies of the protease inhibitor saquinavir (Markowitz et al., 1995 Danner et al., 1995 Collier et al., 1996) and subsequent studies of indinavir (Hammer et al., 1997 Hirsch et al, 1999 Gulick et al., 1997). This study was different from many others that will be cited, and the clinical situation requires some explanation. First, this study did not attempt to compare strategies of multiple ART combinations. Rather, it demonstrated the value of adding a protease inhibitor various ART regimens. In addition to the study design, the patient population was critical for the conclusions of the study. Patients with the most profound immune... 

Eagling VA, Wiltshire H, Whitcombe IW, et al. CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica 2002 32(1) 1-17. 

A major trend in fine chemicals and pharmaceuticals is towards increasingly complex molecules, which translates to a need for high degrees of chemo-, regio- and stereoselectivity. An illustrative example is the synthesis of an intermediate for the Roche HIV protease inhibitor, Saquinavir (Fig. 1.14) [55]. It involves a chemo- and diastereoselective hydrogenation of an aromatic while avoiding racemisation at the stereogenic centre present in the substrate. 

Some protease inhibitors (saquinavir) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41). 

The protease inhibitor saquinavir, propofol, and fluconazole (53,58,59) increased the systemic availability and peak plasma concentrations and prolonged the half-life of midazolam, thus increasing its sedative effects. The dosage of midazolam should be reduced in patients taking these drugs. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Kenyon CJ, Brown F, McClelland, Wilding IR. The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir). Pharm Res 1998 15 417-22. 

The protease inhibitor saquinavir was relaunched in a patented solution-Softgel formulation, providing approximately three times the bioavailability as the original hard-shell formulation. ... 

Ritonavir, an HIV protease inhibitor with peptidelike structure, has an intrinsic water solubility of l.Opg/ml. Norvir is a thermodynamically stable solution formulation containing 100 mg of ritonavir dissolved in a mixture of oleic acid, Cremophor EL, ethanol, and the antioxidant butylated hydroxytoluene (BHT), and filled into soft gelatin capsules. However, Norvir is being replaced by Kaletra oral solution and soft gelatin capsule, which is a combination of 133.3 mg of lopinavir and 33.3 mg ritonavir dissolved in a mixture of oleic acid, polyoxyl 35 castor oil (Cremophor EL), and propylene glycol. The water-insoluble HIV protease inhibitor, saquinavir, is solubilized by a mixture of Vitamin E and medium-chain mono- and diglycerides in 200 mg Fortovase soft gelatin capsules. 

The effect of fluconazole on the steady-state pharmacokinetics of ritonavir and saquinavir has been studied in patients infected with HIV-1 (97). They received the protease inhibitor (saquinavir 1200 mg tds, n = 5, or ritonavir 600 mg bd, n = 3) alone on day 1 and then with fluconazole 400 mg on day 2 and 200 mg on days 3-8. The median increase in saquinavir AUC was 50%, and the median... 

The HIV protease inhibitor saquinavir has hmited and variable oral systemic availability and ritonavir, an inhibitor of CYP450 and P glycoprotein, is widely used to increase its systemic exposure. A small pilot study in three HIV-infected patients has suggested that oral itraconazole can have similar effects on the oral availability of saquinavir (109). Concomitant use of itraconazole 200 mg/day with a combination of saquinavir and two nucleoside reverse transcriptase inhibitors led to a 2.5-to 6.9-fold increase in the AUC of saquinavir, a 2.0- to 5.4-fold increase in peak plasma concentrations, and a 1.6-to 17-fold increase in trough plasma concentrations. The effect of itraconazole on saquinavir was comparable to that of ritonavir. 

Of all protease inhibitors, saquinavir is the most potent in vitro. However, owing to poor systemic availability (less than 4%), it is the least potent of all protease inhibitors in use, although a formulation with increased availability has been marketed. However, when saquinavir is given together with ritonavir, the strong inhibitory effect on CYP3A4 of the latter results in high plasma concentrations of saquinavir. This interaction has been exploited, with favorable results, both in... 

As with other HIV-1 protease inhibitors, saquinavir may be associated with drug interactions as a result of the effect of saquinavir on the hepatic cytochrome P450 oxidase system. Although compared with other HIV protease inhibitors, saquinavir has less of an inhibitory effect on cytochrome P450 isozymes clinically relevant interactions can nevertheless occur. Drug interactions with saquinavir have been reviewed (3). 

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