Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine.
OBJECTIVE
To study the influence of CYP3A4 inhibition by ketoconazole on the disposition of venlafaxine in individuals with different CYP2D6 pheno- and genotypes.


METHODS
In an open two-phase study, 21 healthy volunteers with known CYP2D6 pheno- and genotype [14 extensive metabolisers (EMs), 7 poor metabolisers (PMs)] were given a single oral dose of venlafaxine (50 mg to EMs and 25 mg to PMs). Plasma and urine levels of venlafaxine and its three metabolites were measured and the pharmacokinetics of venlafaxine were determined. After a 2-week washout period, subjects were treated for 2 days with ketoconazole (100 mg twice daily) starting 1 day before the administration of venlafaxine; and the same parameters as for the administration of venlafaxine only were measured.


RESULTS
Data were evaluated from 20 subjects (14 EMs and 6 PMs) who completed the study. The dose-corrected AUC of venlafaxine was on average 2.3 times higher ( P<0.01) and that of its active metabolite O-desmethylvenlafaxine 3.4 times lower ( P<0.0001) in PMs than EMs. There was a good correlation between the debrisoquine metabolic ratio and the ratio between the AUC of venlafaxine and that of O-desmethylvenlafaxine ( Rs=0.93, P<0.002). The majority of subjects showed higher plasma levels of venlafaxine and O-desmethylvenlafaxine upon co-administration of ketoconazole. AUC of venlafaxine significantly increased by 36% and that of O-desmethylvenlafaxine by 26% ( P<0.01). C(max) values increased by 32% and 18%, respectively. The elimination half-life of venlafaxine was unaltered. Three of the PMs displayed marked increases in AUC (81, 126 and 206%) and C(max) (60, 72, 119%) of venlafaxine while the other three showed small or no changes.


CONCLUSIONS
Ketoconazole consistently affected the disposition of venlafaxine in EMs of debrisoquine while the response in PMs was erratic. The precise mechanisms underlying this interaction remain to be elucidated.
Lindh
Jonatan D
JD
Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.
Annas
Anita
A
Meurling
Lennart
L
Dahl
Marja-Liisa
ML
AL-Shurbaji
Ayman
A
D000284:Administration, Oral; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003511:Cyclohexanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003647:Debrisoquin / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000069470:Venlafaxine Hydrochloride; D044465:White People / Q000235:genetics
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D065607:Cytochrome P-450 Enzyme Inhibitors; D000069470:Venlafaxine Hydrochloride; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D003647:Debrisoquin