In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases

Abstract

Montelukast has been recommended as a selective in vitro and in vivo probe of cytochrome P450 (P450) CYP2C8 activity, but its selectivity toward this enzyme remains unclear. We performed detailed characterization of montelukast metabolism in vitro using human liver microsomes (HLMs), expressed P450s, and uridine 59-diphospho-glucuronosyltransferases (UGTs). Kinetic and inhibition experiments performed at therapeutically relevant concentrations reveal that CYP2C8 and CYP2C9 are the principal enzymes responsible for montelukast 36-hydroxylation to 1,2-diol. CYP3A4 was the main catalyst of montelukast sulfoxidation and stereoselective 21-hydroxylation, and multiple P450s participated in montelukast 25-hydroxylation. We confirmed direct glucuronidation of montelukast to an acyl-glucuronide. We also identified a novel peak that appears consistent with an etherglucuronide. Kinetic analysis in HLMs and experiments in expressed UGTs indicate that both metabolites were exclusively formed by UGT1A3. Comparison of in vitro intrinsic clearance in HLMs suggest that direct glucuronidation may play a greater role in the overall metabolism of montelukast than does P450-mediated oxidation, but the in vivo contribution of UGT1A3 needs further testing. In conclusion, our in vitro findings provide new insight toward montelukast metabolism. The utility of montelukast as a probe of CYP2C8 activity may be compromised owing to involvement of multiple P450s and UGT1A3 in its metabolism.

Montelukast Nanocrystals for Transdermal Delivery with Improved Chemical Stability

“…In general, small (molecular weight below 500 Da) compounds with appropriate lipophilicity (log P value between 1 and 3) and a low melting point are more suitable for skin penetration [45]. Moreover, MTK has been reported to be extensively metabolized by multiple cytochrome P450s such as CYP2C8 and CYP2C9 and CYP3A4 and glucuronidase including UGT1A3, which is also abundant in skin layer [46]. Thus, extensive metabolism of MTK molecules in the liver and even skin tissue might contribute large variations.…”

<p>Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children</p>

“…Previous studies have shown that the enzymes of cytochrome P450 (CYP) 2C8, 2C9, 3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A3 are involved in the metabolism of montelukast. [8][9][10][11][12] Meanwhile, some reports have suggested that the organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1 transporters play a part in the permeability of montelukast. 13,14 In clinical practice, the effectiveness of montelukast shows large inter-individual variability.…”

“…13,14 In clinical practice, the effectiveness of montelukast shows large inter-individual variability. 15,16 Variations among genes encoding the metabolizing enzymes or membrane transporters [8][9][10][11]13,14,17 were correlated with the clinical response to montelukast. 18,19 For infants and children, the disposition of the drug is influenced by developmental changes in the body, such as organ maturation and function, as well as composition and amount of plasma proteins.…”

“…20 Meanwhile, age-dependent changes in gastric emptying, intestinal enzyme activity and transporters in infants and children may also alter the bioavailability of a drug. 21 In addition, some studies have suggested that CYP2C8 played an important role in the metabolism of montelukast; [8][9][10] several other studies have demonstrated that a common polymorphism of SLCO2B1, the gene coding for the OATP2B1 transport protein, exhibited a substantial effect on the pharmacokinetics and pharmacodynamics of montelukast. 13,17 Recently, a study reported that the pharmacokinetics of montelukast was determined by OATPs-mediated uptake, along with CYP2C8 metabolism.…”

Amenamevir: Studies of Potential CYP2C8‐ and CYP2B6‐Mediated Pharmacokinetic Interactions With Montelukast and Bupropion in Healthy Volunteers

“…It is metabolized to its primary metabolite methyl‐hydroxymontelukast (M6) via 36‐hydroxylation by CYP2C8, which is also responsible for subsequent conversion to the secondary metabolite montelukast dicarboxylic acid (M4). CYP2C8 is thought to account for 70% to 80% of montelukast's metabolism in vivo, with most of the remainder accounted for by CYP3A4‐mediated conversion to M5a and M5b metabolites: less than 0.2% is eliminated in urine . This, together with its benign safety profile, makes it an appropriate choice as a CYP2C8 probe in healthy subjects. Bupropion is an orally available antidepressant and nonnicotine smoking cessation aid that is thought to exert its activity by reuptake inhibition of norepinephrine and dopamine and by noncompetitive antagonism of nicotinic acetylcholine receptors .…”