title: Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers.
abstract: The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of terfenadine was investigated. Thirteen subjects who completed the study received a single 120 mg dose of terfenadine alone or with concomitant 20 mg sertindole daily. The mean values for terfenadine Cmax (alone: 2.42 +/- 1.48 ng/ml, in combination: 2.99 +/- 1.85 ng/ml) and AUC (29.6 +/- 18.9 vs 37.9 +/- 23.4 ng x hr/ml) did not change statistically significant in the presence of sertindole (p > 0.05). Similarly, the mean Cmax (531 +/- 195 vs 506 +/- 190 ng/ml) and AUC (3,728 +/- 1,163 vs 4,003 +/- 1,739 ng x hr/ml) values of carboxyterfenadine did not change statistically significant in the presence of sertindole (p > 0.05). The other pharmacokinetic parameters of terfenadine and carboxyterfenadine such as Tmax, t1/2, as well as the carboxyterfenadine to terfenadine Cmax and AUC ratios did not change in the presence of sertindole. Although terfenadine is a substrate for CYP3A (cytochrome P-450 3A), while sertindole is a substrate for both CYP2D6 and CYP3A4, the results in this study suggest that sertindole, at a clinical dose, is not an inhibitor of the metabolism of terfenadine.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Abbott laboratories, Abbot Park, IL 60064-3500, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Cao
authors.forename: R
authors.initials: R
authors.lastname: Mack
authors.forename: G R
authors.initials: GR
authors.lastname: Granneman
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004347:Drug Interactions; D005260:Female; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases / Q000737:chemistry; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D016593:Terfenadine / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D007211:Indoles; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; C066304:sertindole