Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe

Schmitt, Christophe; Kaeser, B; Riek, Myriam; Bech, Nuria; Kreuzer, Caroline

doi:10.5414/cpp48192

Cited by 34 publications

(25 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the complete inhibition of p‐glycoprotein in the intestine should lead to the AUC increase 2.1‐fold at most, which is almost the same as the results of the present clinical study, suggesting that p‐glycoprotein function in the intestine is almost fully inhibited by ritonavir. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.3‐fold and 1.5‐fold increase in the C max and AUC 0–72 values of digoxin, another in vivo probe for p‐glycoprotein . Other studies also showed that co‐administration of ritonavir increased the plasma AUC of digoxin by from 22% to 86% .…”

Section: Discussionmentioning

confidence: 98%

“…Some clinical studies showed that coadministration of ritonavir increased the plasma AUC and C max of saquinavir . In order to evaluate the mechanisms behind this interaction, clinical studies have been conducted . In healthy volunteers, the i.v.…”

mentioning

confidence: 99%

“…4,5 In order to evaluate the mechanisms behind this interaction, clinical studies have been conducted. [6][7][8] In healthy volunteers, the i.v. clearance of midazolam, a substrate of CYP3A4, showed a dose-dependent decrease with increasing ritonavir doses.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p‐Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs

Ieiri

Tsunemitsu

Maeda

et al. 2013

The Journal of Clinical Pharma

View full text Add to dashboard Cite

We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC0-24 (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)0-24 ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.

show abstract

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p‐Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs

Ieiri

Tsunemitsu

Maeda

et al. 2013

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…However, the formulation does not contain any excipients that have the potential to inhibit drug efflux. More recent studies using digoxin as a probe in healthy subjects have shown that both saquinavir and ritonavir have inherent potential to inhibit P-gp [19]. In some studies, ritonavir has also been demonstrated to induce P-gp activity [20], suggesting a complex interaction of the drug and transporter which is still not completely understood.…”

Section: Surfactants and Co-solventsmentioning

confidence: 99%

Review and analysis of FDA approved drugs using lipid-based formulations

Savla

Browne

Plassat³

et al. 2017

Drug Development and Industrial Pharmacy

170

View full text Add to dashboard Cite

Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule. ARTICLE HISTORY

show abstract

“…Biliary excretion is the major elimination pathway responsible for almost the entire SQV elimination with < 1% renal excretion [127]. It is an inhibitor of CYP3A4 [131] and CYP3A5 [119] and a weak inhibitor of CYP3A7 [132], with some inhibitory effects on CYP2C9 [133] and is also reported to be a P-gp inhibitor [134].…”

Section: Saquinavirmentioning

confidence: 99%

Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics

Arab‐Alameddine¹,

Décosterd²,

Buclin³

et al. 2011

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

show abstract

Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe

Cited by 34 publications

References 0 publications

Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p‐Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs

Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p‐Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs

Review and analysis of FDA approved drugs using lipid-based formulations

Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics

Contact Info

Product

Resources

About