Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.

The stereospecific determination of fluoxetine and norfluoxetine enantiomers in human plasma by high-pressure liquid chromatography (HPLC) with fluorescence detection.

A quantitative method for the simultaneous HPLC resolution and detection of the enantiomers of (R,S) fluoxetine (F) and their metabolites (R,S) norfluoxetine (N) in human plasma has been developed. F is a serotonin uptake inhibitor used in the treatment of depression and is administered as a racemate. After liquid-liquid extraction and derivatization with (R) napthyl ethyl isocyanate (NEI), the separation and detection of the resultant diasteriomers were achieved using normal phase HPLC and fluorescence. The four NEI diastereomers and the internal standard [(-)-N-methyl-gamma-(2-methylphenoxy) benzenepropanamine hydrochloride], representing the enantiomers S-F, R-F, S-N, and R-N were resolved within 15 min. The assay for each analyte was linear using two concentration ranges of 1-10 and 10-500 ng/ml of human plasma. The precision and accuracy are reported as the coefficient of variation (%CV) and relative error (%RE). The sum of the chiral HPLC results from plasma samples were compared to the achiral gas chromatographic/electron capture (GC/EC) results. The correlation between these two methods, for total F and N, resulted in r2 values of 0.98 and 0.89, respectively. The chiral HPLC method is currently being applied to clinical studies for the evaluation of the enantiomeric disposition of F.

Determination of a potential antiasthmatic compound, tibenelast, and its application to phase I clinical trials.

A sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of tibenelast, 5,6-diethoxybenzo[b]thiophene-2- carboxylic acid, in plasma and urine. The plasma assay involves protein precipitation with 4% trichloroacetic acid, while the urine assay is an automated solid-phase extraction procedure that utilizes the Waters Millilab workstation. The analysis was achieved by reversed-phase HPLC with ultraviolet detection at 313 nm. The quantitation limit of the assay was 50 ng/ml in plasma and 100 ng/ml in urine. The intra-day coefficient of variation for the plasma analysis was between 2.2 and 8.4%, while the overall inter-day coefficient of variation was 5.5 and 6.0% for the high and low calibration curves, respectively. The intra-day coefficient of variation for the urine analysis was between 0.3 and 3.0%, while the inter-day coefficient of variation was 2.1% for both the low and high validation samples. The assay methodology has been used in the evaluation of samples from pharmacokinetic and clinical safety studies.