Quantification of the transporter substrate fexofenadine in cell lysates by liquid chromatography/tandem mass spectrometry.

Drug-drug interactions at transporters present a significant and under-investigated clinical problem. Investigations of specific transporter functions and screening for potential drug-drug interactions, both in vitro and especially in vivo, will require validated experimental probes. Fexofenadine, an approved, well-tolerated drug, is a promising probe for studies of membrane transporter function. Although fexofenadine pharmacokinetics are known to be controlled by transporters, the contributions of individual transporters have not been defined. We have developed a rapid, specific, and sensitive analytical method for quantitation of fexofenadine to support this work. This liquid chromatography/tandem mass spectrometry (LC/MS/MS) method quantifies fexofenadine in cell lysates from in vitro studies using cetirizine as the internal standard. Cell lysates were prepared for analysis by acetonitrile precipitation. Analytes were then separated by gradient reversed-phase chromatography and analyzed by tandem mass spectrometry using the m/z 502.17/466.2 transition for fexofenadine and m/z 389.02/201.1 for cetirizine. The method exhibited a linear dynamic range of 1-500 ng/mL for fexofenadine in cell lysates. The lower limit of quantification was 1 ng/mL with a relative standard deviation of less than 5%. Intra- and inter-day precision and accuracy were within the limits presented in the FDA guidelines for bioanalysis. We also will validate this method to support not only the quantification of fexofenadine, but also other probe drugs for drug-drug interaction studies. This method for quantification will facilitate the use of fexofenadine as a probe drug for characterization of transporter activity.

Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid.

BACKGROUND: The cause and pathogenesis of chronic urticaria are still poorly understood. IgE-independent reactions, are common in adult patients with chronic urticaria, who have daily spontaneous occurrence of weals. H(1)-receptor antagonists (antihistamines) are the major class of therapeutic agents used in the management of urticaria and angioedema. Nevertheless, chronic urticaria is often difficult to treat and may not be controlled by antihistamines alone. It has been postulated that mediators other than histamine, such as kinins, prostaglandin and leukotrienes, may be responsible for some of the symptoms in urticaria which are not controlled by antihistamines. In this study, which was randomized double-blind, placebo-controlled, we compare the clinical efficacy and safety of montelukast (MT) 10 mg given once a day and cetirizine (CET) 10 mg given once a day with placebo (PLA), in the treatment of patients with chronic urticaria who have positive challenge to acetylsalicylic acid (ASA) and/or food additives. PATIENTS AND METHODS: A group of 51 patients, ranging in age from 15 to 71 years, with chronic urticaria and positive challenge to food additives and/or ASA, participated in this study for a period of 4 weeks, starting from a 3-day run-in. The assessment of the efficacy was based on scores of daily urticaria symptoms. RESULTS: MT significantly increased the percentage of symptom-free days for hive and itch. Analysis of frequency distribution of urticaria scores for each symptom gave similar results (MT vs. CET and MT vs. PLA, P < 0.001). The interference with sleep due to their skin condition was also lower in the group treated with MT (P < 0.001). In addition, the median number of days without the rescue medication was significantly higher in the MT group (24 days) than both the CET and the PLA groups (18 days, P < 0.001, and 20 days, P < 0.001, respectively). Finally, a low incidence of adverse events was observed in this study. CONCLUSION: The results of this comparative study demonstrate that montelukast orally administered once a day is very effective for the treatment of cutaneous symptoms in patients with chronic urticaria due to food additives and/or ASA.