Microdose study of a P‐glycoprotein substrate, fexofenadine, using a non‐radioisotope‐labelled drug and LC/MS/MS

Objective:  Fexofenadine is a P‐glycoprotein substrate of low bioavailability. It is primarily excreted into faeces as a parent drug via biliary excretion. The predictability from microdose data for the drug absorbed via transporters such as P‐glycoprotein is not known. Therefore, this study assessed the predictability of therapeutic‐dose pharmacokinetics of fexofenadine from microdosing data using non‐radioisotope‐labelled drug and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS).

[1]  N. Yasui-Furukori,et al.  Different Effects of Three Transporting Inhibitors, Verapamil, Cimetidine, and Probenecid, on Fexofenadine Pharmacokinetics , 2005, Clinical pharmacology and therapeutics.

[2]  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.

[3]  H. Kusuhara,et al.  P-GLYCOPROTEIN PLAYS A MAJOR ROLE IN THE EFFLUX OF FEXOFENADINE IN THE SMALL INTESTINE AND BLOOD-BRAIN BARRIER, BUT ONLY A LIMITED ROLE IN ITS BILIARY EXCRETION , 2005, Drug Metabolism and Disposition.

[4]  Malcolm Rowland,et al.  Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs , 2006, Clinical pharmacology and therapeutics.

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

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

[7]  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.

[8]  Innovation OR Stagnation Challenge and Opportunity on the Critical Path to New Medical Products , 2004 .

[9]  Shiew-Mei Huang,et al.  Effect of St John's wort on the pharmacokinetics of fexofenadine , 2002, Clinical pharmacology and therapeutics.

[10]  R D Combes,et al.  Early microdose drug studies in human volunteers can minimise animal testing: Proceedings of a workshop organised by Volunteers in Research and Testing. , 2003, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[11]  U. Hofmann,et al.  Fexofenadine pharmacokinetics are associated with a polymorphism of the SLCO1B1 gene (encoding OATP1B1). , 2005, British journal of clinical pharmacology.

[12]  R. Colin Garner,et al.  Big physics, small doses: the use of AMS and PET in human microdosing of development drugs , 2003, Nature Reviews Drug Discovery.

[13]  K. Maeda,et al.  INHIBITION OF OAT3-MEDIATED RENAL UPTAKE AS A MECHANISM FOR DRUG-DRUG INTERACTION BETWEEN FEXOFENADINE AND PROBENECID , 2006, Drug Metabolism and Disposition.

[14]  T. Jones,et al.  In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. , 2001, Drug discovery today.

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

[16]  H. Lennernäs,et al.  Transport Characteristics of Fexofenadine in the Caco-2 Cell Model , 2004, Pharmaceutical Research.

[17]  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.

[18]  Bengt Långström,et al.  Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development , 2003, European Journal of Clinical Pharmacology.

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

[20]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[21]  B. Diquet,et al.  Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans , 2004, Fundamental & clinical pharmacology.

[22]  R. C. Garner,et al.  Current perspectives of 14C-isotope measurement in biomedical accelerator mass spectrometry , 2004, Analytical and bioanalytical chemistry.

[23]  Yuichi Sugiyama,et al.  Microdose clinical trial: quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[24]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.