Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine

Abstract

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day). There were no significant alterations of bromocriptine pharmacokinetic parameters after caffeine, although statistical power was very low. With the use of erythromycin, the bromocriptine area under the concentration-time curve standardized to body weight increased significantly by 268%, whereas peak bromocriptine plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Time to achieve Cmax was not altered by erythromycin. We conclude that erythromycin can markedly increase the systemic bioavailability of bromocriptine, which can lead to increased therapeutic or adverse effects, whereas the effects of caffeine require further study.

High affinity of ergopeptides for cytochromes P450 3A

“…This leads to a dramatic decrease in the oxidative metabolism of bromocriptine (or dihydroergotamine), which depends on the same P450 isozyme. This phenomenon could be the origin of the increase of the plasma levels of these alkaloids observed in patients also treated with erythromycin or troleandomycin (Nelson et al, 1990).…”

“…All these results suggest that ergot alkaloids, like bromocriptine and dihydroergotamine, could be metabolized at least in part by P450 3A4 in human liver. This would explain certain problems encountered in patients treated simultaneously with these ergopeptides and a macrolide antibiotic such as erythromycin or troleandomycin (Hayton, 1969;Varoquaux et al, 1981;Ludden, 1985;Nelson et al, 1990). These macrolide antibiotics have been found to greatly inhibit P450s 3A in man by forming stable P450-iron-metabolite complexes (Pessayre et al, 1982;Larrey et al, 1983).…”

“…The metabolism in man of two ergot alkaloids of the ergopeptide type, dihydroergotamine and bromocriptine, has been shown to be inhibited by co-administration of erythromycin or troleandomycin (Nelson et al, 1990;Hayton, 1969;Martinet and Kiechel, 1983;Varoquaux et al, 1981). This suggests that these alkaloids may be oxidized by P45Os 3A in human liver.…”

Increasing Dopaminergic Activity: Effects of L-Dopa and Bromocriptine on Human Sensory Gating

“…2.5 h after oral intake of L-dopa and 1.5 h after oral intake of bromocriptine); L-dopa (LeWitt et al, 1989;Dempski et al, 1989;Yeh et al, 1989), bromocriptine (Drewe et al, 1988;Nelson et al, 1990;Kopitar et al, 1991). Blood sampling, directly followed by the physiological assessments, took place at appropriate intervals during a testday (see below).…”

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

“…For example, rifampin, a known inhibitor of OATP1B-type carriers, 8 can significantly inhibit erythromycin uptake and subsequent metabolism in freshly isolated rat hepatocytes, 9 as well as impair erythromycin metabolism in human subjects undergoing an erythromycin breath test. 10 Moreover, erythromycin can significantly increase the plasma levels of bromocriptine in humans 11 by a mechanism that involves, in part, inhibition of OATP1B1-mediated uptake of bromocryptine in the liver by erythromycin. 12 The aims of the current study were to ( i ) evaluate transport of erythromycin by OATP1B1 in vitro ; ( ii ) determine erythromycin metabolism in mice that are knockout for the related transporter Oatp1b2; and ( iii ) assess the functional impact of germline variation in SLCO1B1 on the metabolism of erythromycin in humans.…”