Reductive metabolism of nabumetone by human liver microsomal and cytosolic fractions: exploratory prediction using inhibitors and substrates as marker probes.

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Citation

Matsumoto K, Hasegawa T, Koyanagi J, Takahashi T, Akimoto M, Sugibayashi K

Reductive metabolism of nabumetone by human liver microsomal and cytosolic fractions: exploratory prediction using inhibitors and substrates as marker probes.

Eur J Drug Metab Pharmacokinet. 2015 Jun;40(2):127-35. doi: 10.1007/s13318-014-0190-0.

PubMed ID
24659525 [ View in PubMed
]
Abstract

The metabolic reduction of nabumetone was examined by inhibition and correlation studies using human liver microsomes and cytosol. This reduction was observed in both fractions, with the V(max) values for reduction activity being approximately fourfold higher, and the V(max)/K(m) values approximately three-fold higher, in the microsomes than in the cytosol. The reduction of nabumetone was inhibited by 18beta-glycyrrhetinic acid, an 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inhibitor, in the microsomal fraction. The reduction activity was also inhibited by quercetin and menadione [carbonyl reductase (CBR) inhibitors], and by phenolphthalein and medroxyprogesterone acetate [potent inhibitors of aldo-keto reductase (AKR) 1C1, 1C2 and 1C4] in the cytosol. A good correlation (r(2) = 0.93) was observed between the reduction of nabumetone and of cortisone, as a marker of 11beta-HSD activity, in the microsomal fractions. There was also an excellent relationship between reduction of nabumetone and of the AKR1C substrates, acetohexamide, and ethacrynic acid (r 2 = 0.92 and 0.93, respectively), in the cytosol fractions. However, a poor correlation was observed between the formation of 4-(6-methoxy-2-naphthyl)-butan-2-ol (MNBO) from nabumetone and CBR activity (with 4-benzoyl pyridine reduction as a CBR substrate) in the cytosol fractions (r(2) = 0.24). These findings indicate that nabumetone may be metabolized by 11beta-HSD in human liver microsomes, and primarily by AKR1C4 in human liver cytosol, although multiple enzymes in the AKR1C subfamily may be involved. It cannot be completely denied that CBR is involved to some extent in the formation of MNBO from nabumetone in the cytosol fraction.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
NabumetoneAldo-keto reductase family 1 member C1ProteinHumans
Unknown
Substrate
Details
NabumetoneAldo-keto reductase family 1 member C2ProteinHumans
Unknown
Substrate
Details
NabumetoneAldo-keto reductase family 1 member C4ProteinHumans
Unknown
Substrate
Details
NabumetoneCorticosteroid 11-beta-dehydrogenase isozyme 1ProteinHumans
Unknown
Substrate
Details
Drug Reactions
Reaction
Details
Details