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Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.

Publication ,  Journal Article
Kharasch, ED; Stubbert, K
Published in: Drug Metab Dispos
December 2013

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) ritonavir-lopinavir 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.

Duke Scholars

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

December 2013

Volume

41

Issue

12

Start / End Page

2166 / 2174

Location

United States

Related Subject Headings

  • Young Adult
  • Ritonavir
  • Pharmacology & Pharmacy
  • Methadone
  • Male
  • Lopinavir
  • Liver
  • Intestinal Mucosa
  • Humans
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
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Kharasch, E. D., & Stubbert, K. (2013). Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir. Drug Metab Dispos, 41(12), 2166–2174. https://doi.org/10.1124/dmd.113.053991
Kharasch, Evan D., and Kristi Stubbert. “Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.Drug Metab Dispos 41, no. 12 (December 2013): 2166–74. https://doi.org/10.1124/dmd.113.053991.
Kharasch ED, Stubbert K. Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir. Drug Metab Dispos. 2013 Dec;41(12):2166–74.
Kharasch, Evan D., and Kristi Stubbert. “Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.Drug Metab Dispos, vol. 41, no. 12, Dec. 2013, pp. 2166–74. Pubmed, doi:10.1124/dmd.113.053991.
Kharasch ED, Stubbert K. Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir. Drug Metab Dispos. 2013 Dec;41(12):2166–2174.
Journal cover image

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

December 2013

Volume

41

Issue

12

Start / End Page

2166 / 2174

Location

United States

Related Subject Headings

  • Young Adult
  • Ritonavir
  • Pharmacology & Pharmacy
  • Methadone
  • Male
  • Lopinavir
  • Liver
  • Intestinal Mucosa
  • Humans
  • Female