CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast

Karonen, Tiina; Neuvonen, Pertti J.; Backman, Janne T.

doi:10.1111/j.1365-2125.2011.04086.x

Cited by 43 publications

(57 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Host-and therapy-related determinants were explored for their potential association with ADRs. We focused on polymorphisms of two genes and alleles with a reported population prevalence of ⩾9%, namely CYP2C8*3, strongly associated with hepatic metabolism of montelukast [22,23], and SLCO2B1 that codes for the transporter OATP2B1 modulating intestinal and blood-brain barrier transport of montelukast [24,25]. Finally, in the nested matched-controlled cohort, we ascertained the relative incidence of neuropsychiatric ADRs leading to drug cessation in the montelukast versus ICS groups.…”

Section: Methodsmentioning

confidence: 99%

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice

et al. 2017

View full text Add to dashboard Cite

@ERSpublicationsThe incidence of children on montelukast with drug cessation due to neuropsychiatric adverse events was >10% http://ow.ly/nCGG30bgjpd ABSTRACT Although montelukast is generally well tolerated, postmarketing studies have reported serious neuropsychiatric adverse drug reactions (ADRs) leading to a United States Food and Drug Administration black box warning. The objective of this study was to determine the incidence of neuropsychiatric ADRs leading to discontinuation of montelukast in asthmatic children.We conducted a retrospective cohort study in children aged 1-17 years initiated on montelukast. In a nested cohort study, children initiated on montelukast as monotherapy or adjunct therapy to inhaled corticosteroids (ICS) were matched to those initiated on ICS monotherapy. A non-leading parental interview served to ascertain the occurrence of any ADRs with any asthma medication, and circumstances related to, and evolution of, the event.Out of the 106 participants who initiated montelukast, most were male (58%), Caucasian (62%) with a median (interquartile range) age of 5 (3-8) years. The incidence (95% CI) of drug cessation due to neuropsychiatric ADRs was 16 (10-26)%, mostly occurring within 2 weeks. Most frequent ADRs were irritability, aggressiveness and sleep disturbances. The relative risk of neuropsychiatric ADRs associated with montelukast versus ICS was 12 (2-90).In the real-life setting, asthmatic children initiated on montelukast experienced a notable risk of neuropsychiatric ADRs leading to drug cessation, that is significantly higher than that associated with ICS.

show abstract

Section: Methodsmentioning

confidence: 99%

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The potential role of CYP2C8 is further supported by the ability of montelukast to tightly bind to the CYP2C8 active site (Schoch et al, 2008) and to potently and competitively inhibit this enzyme in vitro (Walsky et al, 2005). In healthy volunteers, a markedly increased montelukast exposure along with diminished sequential metabolism via the 36-hydroxylation pathway was noted when montelukast was coadministered with gemfibrozil (Karonen et al, 2010(Karonen et al, , 2012. Gemfibrozil glucuronide is a potent mechanism-based inactivator of CYP2C8 (Shitara et al, 2004;Ogilvie et al, 2006;Backman et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The potential for the presence of alternative mechanisms in montelukast disposition is supported by patterns of drug-drug interactions with montelukast. For example, the mechanism-based inactivator of CYP3A4, clarithromycin, increased montelukast AUC 0-' by approximately 144% (Hegazy et al, 2012), whereas itraconazole (a potent CYP3A inhibitor) did not affect its disposition (Karonen et al, 2012). Clarithromycin is not known to inhibit CYP2C8.…”

Section: Introductionmentioning

confidence: 99%

“…Gemfibrozil glucuronide is a potent mechanism-based inactivator of CYP2C8 (Shitara et al, 2004;Ogilvie et al, 2006;Backman et al, 2009). On the basis of the extent of gemfibrozil-montelukast interaction, Karonen et al (2012) suggested that CYP2C8 accounts for ;80% of the total montelukast clearance. As a result, montelukast was recommended as a sensitive probe of CYP2C8 activity in vivo (Karonen et al, 2010(Karonen et al, , 2012.…”

Section: Introductionmentioning

confidence: 99%

“…On the basis of the extent of gemfibrozil-montelukast interaction, Karonen et al (2012) suggested that CYP2C8 accounts for ;80% of the total montelukast clearance. As a result, montelukast was recommended as a sensitive probe of CYP2C8 activity in vivo (Karonen et al, 2010(Karonen et al, , 2012. However, the possibility that this interaction may involve effects of gemfibrozil on other drug disposition proteins in addition to inhibition of CYP2C8 cannot be ruled out.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Cardoso

Oliveira

et al. 2015

Drug Metab Dispos

View full text Add to dashboard Cite

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.

show abstract

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

Dennison

Puri

Warrington

et al. 2018

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Amenamevir (formerly ASP2151) induces cytochrome P450 (CYP)2B6 and CYP3A4 and inhibits CYP2C8. We conducted 2 studies, 1 using montelukast as a probe to assess CYP2C8 and the other bupropion to assess CYP2B6. The montelukast study examined the effect of amenamevir on the pharmacokinetics of montelukast in 24 healthy men: each subject received montelukast 10 mg alone, followed by montelukast 10 mg with amenamevir 400 mg, or vice versa after a washout period. In the bupropion study, 24 subjects received a single dose of 150 mg bupropion on days 1, 15, 22, and 29, and repeated once‐daily doses of 400 mg amenamevir on days 6‐15. Amenamevir increased peak concentration and area under the concentration‐time curve of montelukast by about 22% (ratio 121.7%, 90%CI [114.8, 129.1]; 121% [116.2, 128.4], respectively) with a similar increase in hydroxymontelukast (ratio 121.4%, 90%CI [106.4, 138.5]; 125.6 % [111.3, 141.7]). Amenamevir reduced peak concentration and area under the concentration‐time curve of bupropion by 16% (84.29%, 90%CI [78.00, 91.10]; 84.07%, 90%CI [78.85, 89.63]), with recovery after 1 week; the pharmacokinetics of the primary metabolite hydroxybupropion was unaffected. Thus, amenamevir increased plasma concentrations of montelukast and decreased those of bupropion, but it did not do so enough to require dose adjustment of coadministered substrates of either CYP2C8 or CYP2B6.

show abstract

CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast

Cited by 43 publications

References 38 publications

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice

Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice

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

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

Contact Info

Product

Resources

About