Metabolism of Intravenous Methylnaltrexone in Mice, Rats, Dogs, and Humans

Chandrasekaran, Appavu; Zheng, Tong; Li, Hongshan; Erve, John C. L.; DeMaio, William; Goljer, Igor; McConnell, Oliver J.; Rotshteyn, Yakov; Hultin, T A; Talaat, Rasmy E.; Scatina, JoAnn

doi:10.1124/dmd.109.031179

Cited by 26 publications

(23 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1) and were generally consistent with previous in vivo metabolism observations (Chandrasekaran et al, 2010). Metabolites formed in liver cytosol were identified by LC/MS and had the same retention times and mass spectra as those observed in human plasma as described elsewhere (Chandrasekaran et al, 2010).…”

Section: Carbonyl Reduction Of Mntx In Vitro By Hepatic Cytosol Ofsupporting

confidence: 72%

“…2). The identity of the M2 metabolite peak was confirmed by MS compared with the synthetic standard of M2 (Chandrasekaran et al, 2010). No products were detected when [ 14 C]MNTX was incubated with SULT1A1, SULT1A2, and SULT1A3.…”

Section: Carbonyl Reduction Of Mntx In Vitro By Hepatic Cytosol Ofmentioning

confidence: 81%

“…The primary metabolic pathways for MNTX in humans are sulfation and carbonyl reduction (Chandrasekaran et al, 2010). MNTX was metabolized via glucuronidation, hydroxylation, methylation, sulfation, and carbonyl reduction in nonhuman species.…”

Section: Discussionmentioning

confidence: 99%

“…A significant reversal of the gut transit delay in subjects dependent on chronic methadone treatment was also observed with intravenous MNTX (Yuan et al, 1998(Yuan et al, , 1999(Yuan et al, , 2000. Unlike naltrexone, a structural analog of MNTX without the quaternary amine, which is extensively metabolized in humans (Wall et al, 1981(Wall et al, , 1984, MNTX is only minimally metabolized in humans (Chandrasekaran et al, 2010).…”

mentioning

confidence: 94%

See 3 more Smart Citations

In Vitro Metabolism and Identification of Human Enzymes Involved in the Metabolism of Methylnaltrexone

Zheng

Chandrasekaran²,

Li³

et al. 2010

Drug Metabolism and Disposition

Self Cite

View full text Add to dashboard Cite

ABSTRACT:Methylnaltrexone (MNTX) is a peripherally acting -opioid receptor antagonist and is currently indicated for the treatment of opioidinduced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Sulfation to MNTX-3-sulfate (M2) and carbonyl reduction to methyl-6␣-naltrexol (M4) and methyl-6␤-naltrexol (M5) are the primary metabolic pathways for MNTX in humans. The objectives of this study were to investigate MNTX in vitro metabolism in human and nonclinical species and to identify the human enzymes involved in MNTX metabolism. Of the five commercially available sulfotransferases investigated, only SULT2A1 and SULT1E1 catalyzed M2 formation. Formation of M4 and M5 was catalyzed by NADPH-dependent hepatic cytosolic enzymes, which were identified using selective chemical inhibitors (10 and 100 M) for aldo-keto reductase (AKR) isoforms, short-chain dehydrogenase/reductase including carbonyl reductase, alcohol dehydrogenase, and quinone oxidoreductase. The results were then compared with the effects of the same inhibitors on 6␤-naltrexol formation from naltrexone, a structural analog of MNTX, which is catalyzed mainly by AKR1C4. The AKR1C inhibitor phenolphthalein inhibited MNTX and naltrexone reduction up to 98%. 5␤-Cholanic acid 3␣,7␣-diol, the AKR1C2 inhibitor, and medroxyprogesterone acetate, an inhibitor of AKR1C1, AKR1C2, and AKR1C4, inhibited MNTX reduction up to 67%. Other inhibitors were less potent. In conclusion, the carbonyl reduction of MNTX to M4 and M5 in hepatic cytosol was consistent with previous in vivo observations. AKR1C4 appeared to play a major role in the carbonyl reduction of MNTX, although multiple enzymes in the AKR1C subfamily may be involved. Human SULT2A1 and SULT1E1 were involved in MNTX sulfation.

show abstract

Section: Carbonyl Reduction Of Mntx In Vitro By Hepatic Cytosol Ofsupporting

confidence: 72%

Section: Carbonyl Reduction Of Mntx In Vitro By Hepatic Cytosol Ofmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

See 2 more Smart Citations

In Vitro Metabolism and Identification of Human Enzymes Involved in the Metabolism of Methylnaltrexone

Zheng

Chandrasekaran²,

Li³

et al. 2010

Drug Metabolism and Disposition

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other metabolic pathways included reduction of 6‐oxo function to give 6α‐ and 6β‐methylnaltrexol, hydroxylation, and/or conjugation with glucuronic acid and sulfate. In general, most of the MTNX dose was excreted unchanged in urine …”

Section: Introductionmentioning

confidence: 99%