The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients

Grub, Sibylle; Bryson, Helen; Goggin, T.; Lüdin, Eric; Jorga, Karin

doi:10.1007/s002280100277

Cited by 74 publications

(43 citation statements)

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“…In most cases, coadministration of clarithromycin with PIs caused the inhibition of CYP3A4 and possibly P-gp, resulting in higher AUC of PIs and clarithromycin (Table 3). Similarly, the AUC of saquinavir was elevated by 99% in the presence of erythromycin (Grub et al 2001). In contrast, another macrolide, azithromycin (zithromax), has shown minimal effect on CYP3A4 and did not alter the blood level of indinavir (Foulds et al 1999), and may serve as a better alternative to erythromycin.…”

Section: Interactions Between Pis and Drugs For Opportunistic Infectionsmentioning

confidence: 93%

MDR- and CYP3A4-Mediated Drug–Drug Interactions

Pal

Mitra

2006

Jrnl Neuroimmune Pharm

170

123

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P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug-drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 muM) enhanced the intracellular concentration of (3)H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of (3)H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of (3)H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of (3)H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin, and sparfloxacin are potent inhibitors of P-gp-mediated efflux of 14C erythromycin and (3)H cyclosporin. Simultaneous administration of fluoroquinolones and macrolides could minimize the efflux and metabolism of both of the drugs. Effects of erythromycin and ketoconazole on carbamazepine metabolism were examined. Formation of 10,11-epoxy carbamazepine, a major CBZ metabolite, was significantly inhibited by these agents. Therefore, drug efflux proteins (P-gp, MRPs) and metabolizing enzyme (CYP450) are major factors in drug interactions. Overlapping substrate specificities of these proteins result in complex and sometimes perplexing pharmacokinetic profiles of multidrug regimens. Drug-drug interactions with PIs and other coadministered agents for human immunodeficiency virus (HIV) positive population have been discussed in light of efflux transporters and metabolizing enzymes. This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates.

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Section: Interactions Between Pis and Drugs For Opportunistic Infectionsmentioning

confidence: 93%

MDR- and CYP3A4-Mediated Drug–Drug Interactions

Pal

Mitra

2006

Jrnl Neuroimmune Pharm

170

123

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“…Therefore, rifampicin-mediated CYP induction becomes a serious concern in the treatment of HIV infection (195). After a 14-day rifampicin treatment (600 mg/day), both the AUC po and C max of saquinavir decreased by more than 4-fold in healthy volunteers (196). Similarly, treatment with rifampicin (600 mg/day) for 7 days caused a 5-fold decrease in both the AUC po and C max of nelfinavir (197).…”

Section: Reduction In Therapeutic Efficacymentioning

confidence: 98%

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

2006

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Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.

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“…Unlike P450 inhibition, CYP3A4 induction is not as frequent a problem and is not normally thought to be a safety concern. Induction can lead to inadequate efficacy of coadministered drugs, and it is therefore an undesirable property (Dickinson et al, 2001;Grub et al, 2001). Induction studies have generally been more difficult to conduct experimentally than inhibition studies because induction is an indirect and slow process of gene up-regulation and increased protein expression; however, the advent of newer technologies such as nuclear receptor-reporter and mRNA analyses has partially overcome this problem.…”

mentioning

confidence: 99%

Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction

Shou¹,

Hayashi²,

Pan³

et al. 2008

Drug Metab Dispos

126

121

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ABSTRACT:CYP3A4 induction is not generally considered to be a concern for safety; however, serious therapeutic failures can occur with drugs whose exposure is lower as a result of more rapid metabolic clearance due to induction. Despite the potential therapeutic consequences of induction, little progress has been made in quantitative predictions of CYP3A4 induction-mediated drug-drug interactions (DDIs) from in vitro data. In the present study,

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The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients

Cited by 74 publications

References 0 publications

MDR- and CYP3A4-Mediated Drug–Drug Interactions

MDR- and CYP3A4-Mediated Drug–Drug Interactions

CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications

Modeling, Prediction, and in Vitro in Vivo Correlation of CYP3A4 Induction

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