Effect of Alosetron on the Pharmacokinetics of Fluoxetine

Abstract

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP3A4. Fluoxetine is an antidepressant that is administered as a racemic mixture of equipotent R- and S-enantiomers. Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine. This metabolite is also present as two enantiomers, of which only the S-enantiomer exhibits comparable antidepressant activity. This study was conducted to assess the potential for an effect of alosetron on the pharmacokinetics of fluoxetine. This was an open-label, two-period, nonrandomized, crossover study in 12 healthy female and male volunteers. The pharmacokinetics for both enantiomers of fluoxetine and norfluoxetine were examined following single oral doses of 20 mg fluoxetine, given alone and in combination with alosetron 1 mg twice daily for 15 days. The results showed small delays in peak concentration but no clinically significant effect of alosetron on the pharmacokinetics of S- and R-fluoxetine or S- and R-norfluoxetine. Coadministration of alosetron and fluoxetine was well tolerated by all subjects.

Inhibitory Metabolic Drug Interactions with Newer Psychotropic Drugs: Inclusion in Package Inserts and Influences of Concurrence in Drug Interaction Screening Software

“…The discrete levels of agreementproposedby Landis and Koch were used to interpret the K statistic,"We analyzed the tabulated data using descriptive statistics includingfrequencies and proportions. Logistic regression was used to calculate unad- Prasugrel" Yes Buproplon 22 T1clopldino' Yes b Citaloprarn" Cimetidino Yos b Duloxetlno" Fluvoxamlne Yes b Duloxetine 25 Paroxeline Yos b Escitalopram 24 Clmotldine Yes b Escitalopram 24 Orneprazole" Yes b Fluoxeline 27 Alosetron' No Fluoxetine 21 Desloratadine' No Mlrtazcpine 2t…”

A Promising New Approach for In Silico Prediction of Drug Concentration Profiles for Drug Candidates Lack of Experimental Pharmacokinetic Data

“…As a racemate, we adjusted some of its ADME and PK parameters according to the literature to make the predicted curve much better fitting the experimental data. [11][12][13] The key ADME parameters predicted by ADME Predictor for the 18 drugs were all listed in the Table S1 , including the detail for the adjusted parameters of Fluoxetine. The observed drug concentration data of each template drug was extracted from published concentrationtime (C-T) curves using WebPlotDigitizer (https://automeris.io/WebPlotDigitizer/).…”

Fluoxetine Metabolism and Pharmacological Interactions: The Role of Cytochrome P450

“…Nonetheless, its administration causes only a slight delay in the peak concentration time of FLU and NFLU but no clinically significant effect [96].…”

“…The interaction between alosetron and FLU has been investigated using enantioselective means [96], and it has been found that alosetron has no significant effect on the pharmacokinetic parameters of either enantiomer of FLU or NFLU.…”