Effect of the route of administration on microsomal enzyme induction following repeated administration of methadone in the mouse

Kapeghian, John C.; Burdock, George A.; Masten, Lawrence W.

doi:10.1016/0006-2952(79)90604-x

Cited by 6 publications

(2 citation statements)

References 13 publications

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“…16,17 It is interesting to note that in rats, autoinduction was observed with oral, but not subcutaneous or intraperitoneal methadone, further suggesting route and concentration-dependence of autoinduction. 19,21 …”

Section: Discussionmentioning

confidence: 99%

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Mechanism of Autoinduction of Methadone N-Demethylation in Human Hepatocytes

Campbell¹,

Crafford²,

Williamson³

et al. 2013

Anesthesia &Amp; Analgesia

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Background There is considerable inter-and intraindividual variability in methadone metabolism and clearance. Methadone dosing is particularly challenging during initiation of therapy, due to time-dependent increases in hepatic clearance (autoinduction). Although methadone N-demethylation is catalyzed in vitro by cytochrome P4502B6 (CYP2B6) and CYP3A4, and clearance in vivo depends on CYP2B6, mechanism(s) of autoinduction are incompletely understood. In this investigation we determined mechanism(s) of methadone autoinduction using human hepatocytes. Methods Fresh human hepatocytes were exposed to 0.1-10 μM methadone for 72 hr. Cells were washed and methadone N-demethylation assessed. CYP2B6, CYP3A4, and CYP3A5 mRNA, protein expression (by gel-free high performance liquid chromatography-mass spectrometry) and catalytic activity (bupropion hydroxylation and alfentanil dealkylation for CYP2B6 and CYP3A4/5, respectively) were measured. Mechanisms of CYP induction were characterized using pregnane X receptor and constitutive androstane receptor reporter gene assays. Results Methadone (10 μM) increased methadone N-demethylation 2-fold, CYP2B6 and CYP3A4 mRNA 3-fold, and protein expression 2-fold. CYP3A5 mRNA was unchanged. CYP2B6 and CYP3A4/5 activities increased 2-fold. Induction by methadone enantiomers (R- vs S-methadone) did not differ. Induction was relatively weak compared with maximum induction by phenobarbital and rifampin. Lower methadone concentrations had smaller effects. Methadone was an agonist for the pregnane X receptor but not the constitutive androstane receptor. Conclusions Methadone caused concentration-dependent autoinduction of methadone N-demethylation in human hepatocytes, related to induction of CYP2B6 and CYP3A4 mRNA expression, protein expression, and catalytic activity. Induction was related to pregnane X receptor but not constitutive androstane receptor activation. These in vitro findings provide mechanistic insights into clinical autoinduction of methadone metabolism and clearance.

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Section: Discussionmentioning

confidence: 99%

“…17,18 Methadone autoinduction also occurs in rodents, along with induction of hepatic microsomal enzymes and methadone N-demethylation. 19-21 …”

Section: Introductionmentioning

confidence: 99%