Erythromycin alters the pharmacokinetics of bromocriptine by inhibition of organic anion transporting polypeptide C–mediated uptake

Abstract

reported that erythromycin significantly increased the area under the curve per kilogram of bromocriptine by 286%, and a 4.6-fold greater maximum plasma concentration than that observed with bromocriptine alone was found. In their report the caffeine-bromocriptine interaction was also studied, and no significant interaction was found. The interaction between erythromycin and bromocriptine is clinically significant. However, the mechanism is not known.Erythromycin is a well-known substrate and inhibitor of cytochrome P450 (CYP) 3A4. Most drug-drug interactions involving erythromycin have been attributed to CYP3A4 inhibition. Peyronneau et al 2 indicated that bromocriptine is also a substrate of CYP3A4. We therefore used a human microsome assay to study whether erythromycin could inhibit the metabolism of bromocriptine. Pooled human liver microsomes (BD Biosciences, San Jose, Calif) containing 6200 pmol/mg · min testosterone 6␤-hydroxylation activity were used. The assay was conducted at 0.8-mg/mL protein with or without an NADPH-regenerating system (BD Biosciences) for 10 minutes at 37°C in triplicate. The products were analyzed by HPLC. 3 Even at a high concentration of erythromycin (100 mol/L), the inhibition of bromocriptine (0.5 mol/L) metabolism was only 8%.Organic anion transporting polypeptide C (OATP-C) is a hepatic uptake transporter with a wide range of substrates and inhibitors. 4 We used the OATP-C-overexpressed HEK-293 cells (HEK-OATP-C) 5 to investigate whether bromocriptine is an inhibitor of OATP-C and found that both bromocriptine (50% inhibitory concentration, 0.12 mol/L) and erythromycin (50% inhibitory concentration, 9.20 mol/L) significantly inhibited the OATP-C-mediated uptake of [ 3 H]estradiol-17␤-D-glucuronide (E 2 17␤G). Caffeine, which showed no interaction with bromocriptine, 1 did not affect the uptake of E 2 17␤G. In HEK-OATP-C cells erythromycin significantly inhibited the uptake of bromocriptine by OATP-C. At 0.5 and 1 mol/L of bromocriptine, the values of inhibition of its OATP-C uptake by 100 mol/L of erythromycin were 65% and 58%, respectively. A higher magnitude of inhibition was anticipated in the therapeutic range of bromocriptine (low nano-molar ranges). At the same bromocriptine concentration (0.5 mol/L), the magnitude of erythromycin inhibition on OATP-C is much higher than that for CYP3A4. Rather than inhibiting bromocriptine metabolism, erythromycin is more likely to have inhibited the hepatic uptake of bromocriptine. Nelson et al 1 suggested that erythromycin decreases first-pass metabolism and increases the systemic bioavailability of bromocriptine. Our data support their findings and suggest a mechanism.In conclusion, the results suggested that bromocriptine is a substrate of OATP-C. In the pharmacotherapeutics of Parkinsonism, the bromocriptine dose may need to be adjusted when patients are coadministered other OATP-C inhibitors or substrates. Furthermore, erythromycin may inhibit OATP-C uptake and CYP3A4 metabolism when it is coadministered with other drugs. When dr...

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