Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers.
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.
Wong
S L
SL
Department of Pharmacokinetics and Biopharmaceutics, Abbott laboratories, Abbot Park, IL 60064-3500, USA.
Cao
G
G
Mack
R
R
Granneman
G R
GR
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
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