RT Journal Article
SR Electronic
T1 In Vitro Metabolism and Identification of Human Enzymes Involved in the Metabolism of Methylnaltrexone
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 801
OP 807
DO 10.1124/dmd.110.032169
VO 38
IS 5
A1 Zeen Tong
A1 Appavu Chandrasekaran
A1 Hongshan Li
A1 Yakov Rotshteyn
A1 John C. L. Erve
A1 William DeMaio
A1 Rasmy Talaat
A1 Theresa Hultin
A1 JoAnn Scatina
YR 2010
UL http://dmd.aspetjournals.org/content/38/5/801.abstract
AB Methylnaltrexone (MNTX) is a peripherally acting μ-opioid receptor antagonist and is currently indicated for the treatment of opioid-induced 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-6α-naltrexol (M4) and methyl-6β-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 μM) 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 6β-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%. 5β-Cholanic acid 3α,7α-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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics