Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P-Glycoprotein Activities

Kharasch, E. D.; Bedynek, P S; Walker, Alysa; Whittington, Dale; Hoffer, Christine

doi:10.1038/clpt.2008.102

Cited by 75 publications

(109 citation statements)

References 51 publications

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“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w 13 The possibility of drug-drug interactions must be considered in the treatment of HIV-associated pain. In previous pharmacokinetic studies in healthy volunteers, for instance, the oral bioavailability of alfentanil was increased from 37% to 95% by steady-state ritonavir concentrations [18]. The acute administration of ritonavir reduced the clearance of intravenous fentanyl by 67% [16].…”

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

“…Ritonavir has been shown to be a strong inhibitor of CYP3A both in vitro [38,39] and in vivo [16,18,40,41]. In the present study ritonavir caused a 3-fold mean increase of oxycodone AUC 0-∞ , which is somewhat smaller than that observed after the azole antimycotic voriconazole (3.6-fold increase in oxycodone AUC 0-∞ ), but bigger than that observed for itrazonazole (2.4-fold increase) and telithromycin (1.8-fold increase) [25][26][27].…”

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

“…Ritonavir is a potent CYP3A, CYP2D6 and P-glycoprotein inhibitor [16][17][18]. It has been described to induce CYP1A2, CYP2B6, CYP2C9 and CYP2C19 [19,20].…”

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confidence: 99%

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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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Section: Pharmacodynamic Resultsmentioning

confidence: 99%

Section: Pharmacodynamic Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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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show abstract

“…Hepatic CYP3A activity was evaluated on day 2 using i.v. alfentanil as an in vivo probe (Kharasch et al, 2004b(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron followed 30 minutes later by alfentanil bolus (15 and 5 mg/kg at control and ritonavir-lopinavir sessions, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…First-pass CYP3A activity and intestinal P-gp (and other transporters) activity were evaluated on day 1 using oral alfentanil and fexofenadine as in vivo probes (Kharasch et al, 2004b(Kharasch et al, , 2005(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron (4 mg i.v.)…”

Section: Methodsmentioning

confidence: 99%

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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Drug interactions with methadone: Time to revise the product label

Greenblatt

2014

Clinical Pharm in Drug Dev

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Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P-Glycoprotein Activities

Cited by 75 publications

References 51 publications

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

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

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

Drug interactions with methadone: Time to revise the product label

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