Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-α-methadol in opioid-naive individuals

David E. Moody, Sharon L. Walsh, Douglas E. Rollins, Jennifer A. Neff, Wei Huang

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20 Scopus citations


Background Levo-acetyl-α-methadol (LAAM) exerts most of it μ-agonist activity through the action of its 2 N-demethylation metabolites, norLAAM and dinorLAAM. The N-demethylation of LAAM to norLAAM and norLAAM to dinorLAAM is primarily performed by cytochrome P450s (CYP) in the 3A family. No previous studies have been conducted to determine the effect of in vivo inhibition of CYP3A on the pharmacokinetics and pharmacodynamics of LAAM. Methods Oral LAAM (5 mg/70 kg) was administered on 2 occasions in a single-blind, randomized crossover design to 13 opioid-naive subjects (6 women and 7 men) 1 hour after pretreatment with 400 mg ketoconazole or placebo. Blood and urine samples were collected at defined intervals over 240- and 96-hour periods, respectively; LAAM, norLAAM, and dinorLAAM concentrations were determined by liquid chromatography-tandem mass spectrometry. Physiologic and subjective measures were collected for up to 72 hours. Results Results are presented as the geometric mean with 90% confidence intervals of individual ratios of ketoconazole to placebo sessions. Coadministration of ketoconazole and LAAM resulted in a 3.22-fold (2.53-4.10, P < .001) and 5.29-fold (4.24-6.61, P < .001) increase in the maximum plasma concentration (C max) and area under the curve (AUC) of LAAM. The values for time to C max (t max) of norLAAM and dinorLAAM were increased 2.43-fold (1.92-3.08, P < .001) and 11.6-fold (8.36-16.1, P < .001), with 0.77-fold (0.67-0.87, P < .005) and 0.55-fold (0.49-0.60, P < .001) decreases in their respective C max values. The AUCs of norLAAM and dinorLAAM were increased 2.25-fold (1.96-2.58, P < .001) and 1.21-fold (1.12-1.32, P < .005), respectively. Pupil diameter was significantly decreased by LAAM after both placebo and ketoconazole pretreatment; ketoconazole increased the t max for miosis 2.92-fold (2.01-4.25, P < .001). Other physiologic measures and numerous subjective effects measures were significantly affected by LAAM; however, few significant effects of ketoconazole pretreatment were observed on these outcomes. Conclusion A single dose of ketoconazole causes a significant pharmacokinetic drug interaction with a single dose of LAAM that results in increased LAAM concentrations relative to norLAAM and dinorLAAM at early time points. Coadministration also results in prolongation of the appearance of its active metabolites and a concomitant prolongation of miosis, a sensitive dynamic index of μ-opioid action. The clinically relevant increase in LAAM concentrations and prolongation of plasma LAAM metabolites may affect physiologic function, such as QT intervals, suggesting that coadministration of LAAM and CYP3A4 inhibitors should be contraindicated.

Original languageEnglish
Pages (from-to)154-166
Number of pages13
JournalClinical Pharmacology and Therapeutics
Issue number2
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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