Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.
BACKGROUND
The oral bioavailability of buspirone is very low as a result of extensive first-pass metabolism. Erythromycin and itraconazole are potent inhibitors of CYP3A4, and they increase plasma concentrations and effects of certain drugs, for example, oral midazolam and triazolam. The possible interactions of buspirone with erythromycin and itraconazole have not been studied before.


METHODS
The pharmacokinetics and pharmacodynamics of buspirone were investigated in a randomized, double-blind, double-dummy crossover study with three phases. Eight young healthy volunteers took either 1.5 gm/day erythromycin, 200 mg/day itraconazole, or placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. Timed blood samples were collected up to 18 hours, and the effects of buspirone were measured with four psychomotor tests up to 8 hours.


RESULTS
Erythromycin and itraconazole increased the mean area under the plasma concentration-time curve from time zero to infinity [AUC(0-infinity] of buspirone about sixfold (p < 0.05) and 19-fold (p < 0.01), respectively, compared with placebo. The mean peak plasma concentration (Cmax) of buspirone was increased about fivefold (p < 0.01) and 13-fold (p < 0.01) by erythromycin and itraconazole, respectively. These interactions were evident in each subject, although a striking interindividual variability in the extent of both interactions was observed. The elimination half-life of buspirone did not seem to be prolonged by either erythromycin or itraconazole. The effect of itraconazole on the Cmax and AUC(0-infinity) of buspirone was significantly (p < 0.01) greater than that of erythromycin. The greatly elevated plasma buspirone concentrations resulted in increased (p < 0.05) pharmacodynamic effects (as measured by the Digit Symbol Substitution test and the Critical Flicker Fusion test) and in side effects of buspirone.


CONCLUSIONS
Both erythromycin and itraconazole greatly increased plasma buspirone concentrations, obviously by inhibiting its CYP3A4-mediated first-pass metabolism. These pharmacokinetic interactions were accompanied by impairment of psychomotor performance and side effects of buspirone. The dose of buspirone should be greatly reduced during concomitant treatment with erythromycin, itraconazole, or other potent inhibitors of CYP3A4.
Kivistö
K T
KT
Department of Clinical Pharmacology, University of Helsinki, Finland.
Lamberg
T S
TS
Kantola
T
T
Neuvonen
P J
PJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D002065:Buspirone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D017366:Serotonin Receptor Agonists; D017964:Itraconazole; D004917:Erythromycin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002065:Buspirone