Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses

Shinderman, Marc; Maxwell, Sarz; Brawand-Amey, Marlyse; Golay, Kerry Powell; Baumann, Pierre; Eap, Chin B.

doi:10.1016/s0376-8716(02)00320-4

Cited by 41 publications

(36 citation statements)

References 29 publications

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“…Similar to cyclosporine, midazolam is also almost entirely eliminated by metabolism and principally by cytochrome P450 3A [13,14] . Methadone is also metabolised via the cytochrome P450 3A pathway [15] . Cyclosporine or methadone have an induction of the cytochrome P450 3A pathway which may lead to rapid metabolism of midazolam and thus a higher dose requirement.…”

Section: Discussionmentioning

confidence: 99%

Sedative Drug Requirements during Flexible Bronchoscopy

Chhajed

Wallner²,

Stolz³

et al. 2005

Respiration

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Background: There is a paucity of data comparing doses of sedative medication during bronchoscopy in immunosuppressed and non-immunosuppressed patients. Objectives: The aim of this study was to define the sedative medication doses used in specific patient groups during bronchoscopy. Methods: Bronchoscopy was performed under local anesthesia, sedation with intermittent boluses of intravenous midazolam and intravenous hydrocodone 5 mg. Two hundred and thirty-nine consecutive bronchoalveolar lavage procedures were included. Procedures in non-immunosuppressed patients were classified as controls (n = 91). Procedures in immunosuppressed patients who received midazolam consisted of stem cell transplant (34), solid organ transplant (25), chemotherapy (33), HIV with drug abuse (10), HIV (5), prednisone (17) and immunosuppression for other diseases (12). Intravenous propofol was administered during 12 procedures due to inability to achieve optimal sedation with midazolam in a previous bronchoscopy (stem cell transplant recipient 1, lung transplant for cystic fibrosis 5) and during the same bronchoscopy due to inadequate sedation with a high dose of midazolam – renal transplant recipient 1, drug abuse (HIV 1, renal transplant recipient 1), bronchoscopy combined with gastroscopy (2) and a hypoxemic patient (1). The mean dose of propofol administered was 2.8 ± 1.3 mg/kg. Results: Midazolam requirement was significantly higher in patients with stem cell transplantation (0.09 ± 0.05 mg/kg) compared with controls (0.06 ± 0.03 mg/kg; p = 0.0002). In the HIV patients with drug abuse (0.12 ± 0.10 mg/kg), there was a tendency for the need of a higher dose of midazolam compared with the control group (p = 0.0754). Conclusion: Stem cell transplant recipients and selected HIV patients with drug abuse need higher doses of midazolam for bronchoscopy.

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Section: Discussionmentioning

confidence: 99%

Sedative Drug Requirements during Flexible Bronchoscopy

Chhajed

Wallner²,

Stolz³

et al. 2005

Respiration

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“…The cytochrome P-450 (CYP) enzymes responsible for methadone metabolism remain controversial; CYP2B6 and CYP3A4 are suggested as main pathways, with less involvement of CYP1A2 and CYP2D6 [2][3][4]. Oxycodone is mainly metabolized by CYP3A4 and CYP2D6 [4,5]. Morphine is metabolized to morphine-3-glucuronide (M3G) and the active morphine-6-glucuronide (M6G) via UGT2B7 [6].…”

Section: Introductionmentioning

confidence: 99%

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Moksnes

Kaasa

Paulsen

et al. 2012

Eur J Clin Pharmacol

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“…Methadone N-demethylation in human liver microsomes and in vivo has historically been attributed to CYP3A4 (Iribarne et al, 1996;Moody et al, 1997;Foster et al, 1999;Shinderman et al, 2003;Wang and DeVane, 2003). More recently, in vitro experiments at therapeutic concentrations have shown a predominant role for CYP2B6 (Gerber et al, 2004;Kharasch et al, 2004;Totah et al, 2004) and minor activity with CYP2C19 (Foster et al, 1999;Gerber et al, 2004).…”

mentioning

confidence: 99%

Enantiomeric Metabolic Interactions and Stereoselective Human Methadone Metabolism

Totah

Allen

Sheffels

et al. 2007

J Pharmacol Exp Ther

100

134

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Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6-but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic interactions may confer variability in methadone disposition.The chiral opioid methadone, a mainstay in the treatment of opiate addiction and acute and chronic pain, is used clinically as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective; there is considerable interindividual variability in clearance (up to 100-fold) and plasma R/S ratios (4-fold), and methadone clearance is subject to numerous drug interactions (Plummer et al., 1988;Eap et al., 2002). Nevertheless, the mechanism of stereoselective clearance and metabolism and interindividual variability remains poorly understood. Methadone elimination is due mainly to metabolic clearance (Anggard et al., 1975). The main pathway of methadone metabolism is N-demethylation to inactive 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). A minor reductive route to normethadol is not cytochrome P450-mediated. The significant correlation between methadone clearance and the plasma EDDP/methadone area under the curve ratios suggest that N-dem...

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Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses

Cited by 41 publications

References 29 publications

Sedative Drug Requirements during Flexible Bronchoscopy

Sedative Drug Requirements during Flexible Bronchoscopy

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Enantiomeric Metabolic Interactions and Stereoselective Human Methadone Metabolism

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