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 α‐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 area 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 with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects. Clinical Pharmacology & Therapeutics (2001) 70, 142–148; doi: 10.1067/mcp.2001.117286