Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected Patients

Wyen, Christoph; Fuhr, Uwe; Frank, Dorothee; Aarnoutse, R.E.; Klaassen, Tobias; Lazar, Andreas; Seeringer, Angela; Doroshyenko, Oxana; Kirchheiner, J; Abdulrazik, F; Schmeißer, Norbert; Lehmann, Clara; Hein, W.; Schömig, Edgar; Burger, D.M.; Fätkenheuer, Gerd; Jetter, Alexander

doi:10.1038/sj.clpt.6100452

Cited by 72 publications

(72 citation statements)

References 46 publications

(98 reference statements)

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“…Similar conclusions were articulated previously (van Heeswijk et al, 2006) and also were reached using oral digoxin, considered to quantify primarily intestinal P-gp activity (Wyen et al, 2008). Ritonavir-lopinavir increased digoxin AUC and C max 1.8-and 1.6-fold, respectively, interpreted as P-gp inhibition (Wyen et al, 2008). Ritonavir alone at steady state (300 or 400 mg twice daily) increased digoxin AUC 1.4-to 1.9-fold (Ding et al, 2004;Kirby et al, 2012).…”

Section: Discussionsupporting

confidence: 87%

“…Changes in fexofenadine AUC caused by ritonavir-lopinavir are consistent with decreased fexofenadine intestinal efflux and acute inhibition of P-gp, with partial P-gp induction (yet continued net P-gp inhibition) on continuing exposure. Similar conclusions were articulated previously (van Heeswijk et al, 2006) and also were reached using oral digoxin, considered to quantify primarily intestinal P-gp activity (Wyen et al, 2008). Ritonavir-lopinavir increased digoxin AUC and C max 1.8-and 1.6-fold, respectively, interpreted as P-gp inhibition (Wyen et al, 2008).…”

Section: Discussionsupporting

confidence: 81%

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Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 81%

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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“…After lopinavir/ritonavir, the geometric mean ratio for oxymorphone AUC was increased by 2.7-fold. Earlier studies have reported CYP2D6 inhibition during lopinavir/ritonavir [17,24].…”

Section: Pharmacodynamic Resultsmentioning

confidence: 98%

“…It is a substrate and inhibitor of CYP3A4 and to a lesser extent CYP2D6, and an inducer of CYP1A2, 2B6, 2C9 and 2C19 [23,24] which makes it prone to cytochrome P450-mediated interactions.…”

Section: Discussionmentioning

confidence: 99%

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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To cite this version:Methods: A randomized crossover study design with 3 phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioural effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis.Results: Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-(range 1.9-to 4.3-fold; P<0.001) and 2.6-fold (range 1.9-to 3.3-fold; P<0.001). The mean (± SD) elimination half-life prolonged after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P<0.001) and 5.7 ± 0.9 h (P<0.001), respectively. Both ritonavir (P<0.001) and lopinavir/ritonavir (P<0.05) increased the self-reported drug effect of oxycodone. Conclusions:Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse-effects.

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“…It is still equivocal whether long-term administration of ritonavir may also lead to a certain induction of CYP3A enzymes [15]. However, studies both in healthy volunteers [16] and patients [17] do not support CYP3A4 induction.…”

Section: Introductionmentioning

confidence: 99%

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Corti

Heck

Rentsch

et al. 2009

Eur J Clin Pharmacol

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Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers Abstract BACKGROUND: Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir. METHODS: Sixteen healthy volunteers were administered a single oral dose of 1,000 mg mebendazole or 400 mg albendazole (2 x n = 8). AUC, C(max), and t(1/2) of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg bid. RESULTS: Pharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC(0-24) (27 and 43% of baseline for albendazole and mebendazole, respectively) and C(max) (26 and 41% of baseline, respectively). CONCLUSION: The AUC(0-24) of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitors.

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Effect of an Antiretroviral Regimen Containing Ritonavir Boosted Lopinavir on Intestinal and Hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected Patients

Cited by 72 publications

References 46 publications

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

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