Erythromycin increases plasma concentrations of α-dihydroergocryptine in humans

Objective. Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)-inhibiting agents such as erythromycin and the dopamine agonist alpha -dihydroergocryptine (DHEC). Methods. The study was carried out as a single-center, controlled, nonblinded, 2-way crossover clinical trial with randomly allocated period-balanced sequences investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4-day treatment (days -2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2-25.1 kg (.) m(-2)) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol. Results. The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the a-rea under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24-hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay). Conclusions. The concomitant use of erythromycin or similarly CYP3A4-inhibiting agents along, vith direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic; exposure, which may induce exaggerated dopaminergic effects.