Absence of interaction between erythromycin and a single dose of clozapine.
OBJECTIVE
To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine.


METHODS
Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0-12 h.


RESULTS
There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h x l(-1) in the control phase and 1180 (659) nmol h x l(-1) in the erythromycin phase), terminal halflives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol x l(-1) and 77 (40) nmol x l(-1), respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l x h(-1) and 46 (37) l x h(-1), respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l x h(-1) and 7.8 (9.4) l x h(-1), respectively) or to desmethyl-clozapine (1.5 (1.3) l x h(-1) and 1.8 (1.7) l x h(-1), respectively) or in renal clearances of clozapine (0.8 (0.5) l x h(-1) and 1.0 (0.7) l x h(-1), respectively) between the two phases.


CONCLUSIONS
These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.
Hägg
S
S
Division of Clinical Pharmacology, Norrland University Hospital, Umeå, Sweden. staffan.hagg@pharm.umu.se
Spigset
O
O
Mjörndal
T
T
Granberg
K
K
Persbo-Lundqvist
G
G
Dahlqvist
R
R
D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D003024:Clozapine / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004917:Erythromycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*
D000900:Anti-Bacterial Agents; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004917:Erythromycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003024:Clozapine