The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Recently, we have shown that the plasma concentration of R-fexofenadine is greater than that of the S-enantiomer. Although itraconazole co-administration is known to increase the bioavailability of a racemic mixture of fexofenadine, little is known about the stereoselective inhibition of P-gp activity by itraconazole. WHAT THIS STUDY ADDS This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a an inhibitor of P-gp. AIMS The aim of this study was to determine the inhibitory effect of itraconazole, a P-glycoprotein (P-gp) inhibitor, on the stereoselective pharmacokinetics of fexofenadine. METHODS A two-way double-blind, placebo-controlled crossover study was performed with a 2-week washout period. Twelve healthy volunteers received either itraconazole 200 mg or matched placebo in a randomized fashion with a single oral dose of fexofenadine 60 mg simultaneously. The plasma concentrations and the amount of urinary excretion (Ae) of fexofenadine enantiomers were measured up to 24 h after dosing. RESULTS After placebo administration, mean AUC(0,24 h) of S- and R-fexofenadine was 474 ng ml(-1) h (95% CI 311, 638) and 798 ng ml(-1) h (95% CI 497, 1101), respectively. Itraconazole affected the pharmacokinetic parameters of S-fexofenadine more, and increased AUC(0,24 h) of S-fexofenadine and R-fexofenadine by 4.0-fold (95% CI of differences 2.8, 5.3; P < 0.001) and by 3.1-fold (95% CI of differences 2.2, 4.0; P = 0.014), respectively, and Ae(0,24 h) of S-fexofenadine and R-fexofenadine by 3.6-fold (95% CI of differences 2.6, 4.5; P < 0.001) and by 2.9-fold (95% CI of differences 2.1, 3.8; P < 0.001), respectively. Additionally, the R : S ratio for AUC(0,24 h) and Ae(0,24 h) were significantly reduced in the itraconazole phase, while t(max), t(1/2) and renal clearance were constant during the study. CONCLUSIONS This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a P-gp inhibitor. However, further study will be needed because the different affinities of the two enantiomers for P-gp have not been supported by in vitro studies.

[1]  R. Kim,et al.  Intestinal Drug Transporter Expression and the Impact of Grapefruit Juice in Humans , 2007, Clinical pharmacology and therapeutics.

[2]  M. Miura,et al.  Pharmacokinetics of fexofenadine enantiomers in healthy subjects. , 2007, Chirality.

[3]  M. Miura,et al.  Determination of fexofenadine enantiomers in human plasma with high-performance liquid chromatography. , 2007, Journal of pharmaceutical and biomedical analysis.

[4]  Mikiko Shimizu,et al.  Lack of Dose-Dependent Effects of Itraconazole on the Pharmacokinetic Interaction with Fexofenadine , 2006, Drug Metabolism and Disposition.

[5]  Mikiko Shimizu,et al.  Effects of single and multiple doses of itraconazole on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. , 2006, British journal of clinical pharmacology.

[6]  Mikiko Shimizu,et al.  Sensitive Determination of Itraconazole and Its Active Metabolite in Human Plasma by Column-switching High-performance Liquid Chromatography With Ultraviolet Detection , 2006, Therapeutic drug monitoring.

[7]  Mark Lubberink,et al.  Effect of age on functional P‐glycoprotein in the blood‐brain barrier measured by use of (R)‐[11C]verapamil and positron emission tomography , 2006, Clinical pharmacology and therapeutics.

[8]  Mikiko Shimizu,et al.  Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. , 2006, British journal of clinical pharmacology.

[9]  I. Cascorbi,et al.  Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. , 2006, British journal of clinical pharmacology.

[10]  J. Gorski,et al.  The effect of short‐ and long‐term administration of verapamil on the disposition of cytochrome P450 3A and P‐glycoprotein substrates , 2006, Clinical pharmacology and therapeutics.

[11]  Kazuya Maeda,et al.  CONTRIBUTION OF OATP (ORGANIC ANION-TRANSPORTING POLYPEPTIDE) FAMILY TRANSPORTERS TO THE HEPATIC UPTAKE OF FEXOFENADINE IN HUMANS , 2005, Drug Metabolism and Disposition.

[12]  Jae-Gook Shin,et al.  Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism , 2005, Clinical pharmacology and therapeutics.

[13]  J. Nezu,et al.  Functional Characterization of pH-Sensitive Organic Anion Transporting Polypeptide OATP-B in Human , 2004, Journal of Pharmacology and Experimental Therapeutics.

[14]  M. Gumbleton,et al.  Stereoselective and Concentration-Dependent Polarized Epithelial Permeability of a Series of Phosphoramidate Triester Prodrugs of d4T: An in Vitro Study in Caco-2 and Madin-Darby Canine Kidney Cell Monolayers , 2003, Journal of Pharmacology and Experimental Therapeutics.

[15]  M. Fromm,et al.  Importance of P‐glycoprotein for drug disposition in humans , 2003, European journal of clinical investigation.

[16]  R. Kim,et al.  Organic anion‐transporting polypeptide (OATP) transporter family and drug disposition , 2003, European journal of clinical investigation.

[17]  R. Boellaard,et al.  (R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation. , 2003, Nuclear medicine and biology.

[18]  Jiunn H. Lin,et al.  Role of P-Glycoprotein in Pharmacokinetics , 2003, Clinical pharmacokinetics.

[19]  R. Kim.  Transporters and xenobiotic disposition. , 2002, Toxicology.

[20]  L. Benet,et al.  Functional characterization of monocarboxylic acid, large neutral amino acid, bile acid and peptide transporters, and P-glycoprotein in MDCK and Caco-2 cells. , 2002, Journal of pharmaceutical sciences.

[21]  D. Greenblatt,et al.  Fexofenadine Transport in Caco‐2 Cells: Inhibition with Verapamil and Ritonavir , 2002, Journal of clinical pharmacology.

[22]  Werner Siegmund,et al.  The effects of the human MDR1 genotype on the expression of duodenal P‐glycoprotein and disposition of the probe drug talinolol , 2002, Clinical pharmacology and therapeutics.

[23]  G. Hooiveld,et al.  Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P‐glycoproteins , 2002, British journal of pharmacology.

[24]  H. Kroemer,et al.  Stereoselective disposition of talinolol in man. , 2002, Journal of pharmaceutical sciences.

[25]  P. Dawson,et al.  Fruit juices inhibit organic anion transporting polypeptide–mediated drug uptake to decrease the oral availability of fexofenadine , 2002, Clinical pharmacology and therapeutics.

[26]  B. Haehner‐Daniels,et al.  The effect of rifampin administration on the disposition of fexofenadine , 2001, Clinical pharmacology and therapeutics.

[27]  T. Andersson,et al.  Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites. , 2000, International journal of clinical pharmacology and therapeutics.

[28]  B. Jarvis,et al.  Fexofenadine , 2000, Drugs.

[29]  G R Wilkinson,et al.  OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[30]  D. J. Pack,et al.  Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16 455) and its enantiomers in healthy male volunteers , 1998, Biopharmaceutics & drug disposition.

[31]  J. Molnár,et al.  The role of stereoselectivity of chemosensitizers in the reversal of multidrug resistance of mouse lymphoma cells. , 1998, Anticancer Research.

[32]  H Lennernäs,et al.  The Absence of Stereoselective P‐Glycoprotein‐mediated Transport of R/S‐Verapamil Across the Rat Jejunum , 1998, The Journal of pharmacy and pharmacology.

[33]  M. Dietel,et al.  Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. , 1992, Biochemical pharmacology.

[34]  M C Willingham,et al.  Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.