Effect of ponsinomycin on the pharmacokinetics of dihydroergotamine administered orally

Abstract

Ponsinomycin is a new macrolide antibiotic. Its effect on DHE pharmacokinetics was investigated in this study. Twelve young healthy volunteers received a single 9 mg oral dose of DHE before and on the 8th day of treatment (800 mg twice daily) with ponsinomycin. DHE was assayed in plasma by RIA. Because of low plasma levels, only peak concentrations could be accurately compared for a ponsinomycin effect. We observed a 3-40-fold increase in maximum DHE plasma levels in the majority of cases and a much more important effect on one occasion, when DHE was administered in the presence of ponsinomycin. These data are consistent with an increase of DHE bioavailability in the presence of ponsinomycin, probably related to a reduction of its first-pass elimination. This pharmacokinetic interaction is likely to have clinical consequences and administration of ponsinomycin should be avoided in patients treated orally with DHE.

Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans

“…In the early 1980s, researchers attributed the very low bioavailability of orally administered DHE to high first-pass metabolism (3) and conversion to the active metabolite 8’-OH-DHE (4), later clarified to occur through liver CYP3A4 metabolism (5). Concern over potential drug interactions with potent CYP3A4 inhibitors such as macrolide antibiotics and protease inhibitors (6,7) and case reports of apparent drug interactions with clinical sequelae (8,9) contributed to the establishment of labeling warning against concomitant use of those medications with DHE. Over time other routes, including intravenous (IV), subcutaneous, intramuscular and intranasal, were utilized more frequently than oral administration of DHE; however there are few studies that establish the metabolism and potential drug interactions of DHE administered through these routes.…”

Lack of effect of ponsinomycin on the pharmacokinetics of nicoumalone enantiomers.

“…Ponsinomycin, previously named miocamycin, is a new semi-synthetic macrolide. It is extensively metabolized in vivo (Couet et al, 1989a(Couet et al, , 1990aFucaya et al, 1981;Schomura et al, 1981), and while it has no or only minor effect on theophylline disposition (Couet et al, 1989b;Principi et al, 1987), it has been shown to alter the kinetics of carbamazepine (Couet et al, 1990b), cyclosporin (Couet et al, 1990c) and dihydroergotamine (Couet et al, 1990d). Limited observations suggested that macrolides may interfere with the pharmacokinetics of oral anticoagulants (Ludden, 1985), and administration of macrolides to patients treated with oral anticoagulants is currently considered to be potentially hazardous.…”