Abstract
Objective
Montelukast, a leukotriene receptor antagonist, is used in the treatment of asthma. The objective of the study reported here was to determine whether multiple doses of clarithromycin or fluconazole affect the pharmacokinetics of montelukast.
Methods
This was a four-phase cross-over study with a washout period of 2 weeks between phases. In phase 1, 12 volunteers received a single oral dose of 10 mg montelukast. In phase 2, the volunteers received a single, oral dose of 1,000 mg clarithromycin once daily for 2 days, followed by, on day 3, a single oral dose of 10 mg montelukast co-administered with clarithromycin. In phase 3, a single oral dose of 50 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 50 mg fluconazole. In the last phase (phase 4), a single oral dose of 150 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 150 mg fluconazole. The plasma concentration of montelukast was measured by high performance liquid chromatography for 24 h.
Results
Following clarithromycin co-administration, the area under the concentration–time curve from zero to infinity ( AUC0-∞) of montelukast increased by 144% [90% confidence interval (CI) 2.03–2.86]. The co-administration of a single oral dose of 150 and 50 mg fluconazole decreased the montelukast AUC0–∞ by 30.7 (90% CI 0.53–0.81) and 38.8% (90% CI 0.57–0.69), respectively.
Conclusions
Clarithromycin increased the plasma concentrations of montelukast whereas fluconazole reduced the plasma concentrations of montelukast. The mechanism of the interaction is probably due to interference of the interacting drugs with transporters mediating the uptake of montelukast.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Harmanci K, Bakirtas A, Turktas I, Degim T (2006) Oral montelukast treatment of preschool-aged children with acute asthma. Ann Allergy Asthma Immunol 96(5):731–735
Mougey EB, Feng H, Castro MG, Irvin GC, Lima JJ (2009) Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics 19(2):129–138
Cheng H, Leff JA, Amin R, Gertz BJ, De Smet M, Noonan N, Rogers JD, Malbecq W, Meisner D, Somers G (1996) Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Pharm Res 13:445–448
Merck. Singulair prescribing information. Available from: www.singulair.com/montelukast_sodium/singulair/consumer/adult/asthma/product_information/pi/index.jsp . Accessed 12 Feb 2010
Chiba M, Xu X, Nishime JA, Balani SK, Lin JH (1997) Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist in humans. Drug Metab Dispos 25(11):1282–1287
Filppula AM, Laitila J, Neuvonen PJ, Backman JT (2011) Reevaluation of the microsomal metabolism of montelukast: major contribution by CYP2C8 at clinically relevant concentrations. Drug Metab Dispos 39(5):904–911
Karonen T, Filppula A, Laitila J, Niemi M, Neuvonen PJ, Backman JT (2010) Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast. Clin Pharmacol Ther 88:223–230
Karonen T, Neuvonen PJ, Backman JT (2012) CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast. Br J Clin Pharmacol 73:257–267
Quinney SK, Zhang X, Lucksiri A, Gorski JC, Li L, Hall SD (2010) Physiologically-based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin. Drug Metab Dispos 38:241–248
Eberl S, Renner B, Neubert A, Reisig M, Bachmakov I, König J, Dörje F, Mürdter TE, Ackermann A, Dormann H, Gassmann KG, Hahn EG, Zierhut S, Brune K, Fromm MF (2007) Role of p-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmacoepidemiological studies. Clin Pharmacokinet 46(12):1039–1049
Alsarra IA (2004) Development of a stability-indicating HPLC method for the Determination of montelukast in tablets and human plasma, and its applications to pharmacokinetic and stability studies. Saudi Med J 12(4):136–143
Lee AJ, Maddix DS (2001) Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother 35(1):26–31
Brophy DF, Israel DS, Pastor A, Gillotin C, Chittick GE, Symonds WT, Lou Y, Sadler BM, Polk RE (2000) Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers. Antimicrob Agents Ch 44(4):978–984
Hedaya MA, El-Afify DR, El-Maghraby GM (2006) The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers. Biopharm Drug Dispos 27(2):103–110
Zhou S, Chan E, Li X, Huang M (2005) Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4. Ther Clin Risk Manag 1(1):3–13
Seithel A, Eberl S, Singer K, Auge D, Heinkele G, Wolf NB, Dörje F, Fromm MF, König J (2007) The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos 35(5):779–86
Lan T, Rao A, Haywood J, Davis CB, Han C, Garver E, Dawson PA (2009) Interaction of macrolide antibiotics with intestinally expressed human and rat organic anion-transporting polypeptides. Drug Metab Dispos 37(12):2375–82
Niwa T, Shiraga T, Takagi A, Zasshi Y (2005) Drug-drug interaction of antifungal drugs. Clin Pharmacol Ther 125(10):795–805
Kaukonen KM, Olkkola KT, Neuvonen PJ (1998) Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 53:445–449
Niemi M, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ, Kivist KT (2001) Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharmacol Ther 69(4):194–200
Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, Amidon GL (2004) Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 12(1):85–96
Huang L, Berry L, Ganga S, Janosky B, Chen A, Roberts J, Colletti AE, Lin MH (2010) Relationship between passive permeability, efflux, and predictability of clearance from in vitro metabolic intrinsic clearance. Drug Metab Dispos 38(2):223–231
Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, Wang J, Sylvester J, Holbrook J, Wise R, Weiss ST, Barnes K (2006) Influence of leukotriene pathway polymorphisms on response to montelukastin asthma. Am J Respir Crit Care Med 173(4):379–385
Zaghloul IY, Asiri AY, Alnaim LS, Al-Hadiya BM (2009) Co-administration of fluoxetine alters the steady state pharmacokinetics of fluconazole after multiple oral administration in dogs. Scholarly Research Exchange 834879. doi:10.3814/2009/834879
Lennernas H (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42:1141–1160
Brüggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE, Burger DM (2009) Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 48(10):1441–58
Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW (2002) Interaction of common azole antifungals with P-glycoprotein. Antimicrob Agents Chemother 46:160–165
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hegazy, S.K., Mabrouk, M.M., Elsisi, A.E. et al. Effect of clarithromycin and fluconazole on the pharmacokinetics of montelukast in human volunteers. Eur J Clin Pharmacol 68, 1275–1280 (2012). https://doi.org/10.1007/s00228-012-1239-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-012-1239-0