Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson's disease.

This study investigated whether chronic coadministration of alpha-dihydroergocryptine (DHEC) altered the plasma pharmacokinetics of individualized treatments with levodopa in 12 patients with Parkinson's disease. Steady-state pharmacokinetics of plasma levodopa (L-Dopa) under combined treatment were compared with those under treatment with L-Dopa alone. There was no evidence of increased exposure to L-Dopa caused by concomitant treatment with DHEC. In contrast, additional treatment with DHEC reduced the overall exposure to L-Dopa (17.5% reduction in area under the curve; 95% CI: 23%-6%). This effect was small but statistically significant for the area under the plasma concentration-time curve, whereas tmax (time of maximum plasma concentration) and peak-to-trough fluctuation were not affected. Cmax (maximum plasma concentration), on average, was reduced to a similar extent (-14.5%; 95% CI: 38% to -17%), albeit not significantly. The magnitude of the interaction does not suggest changing the current clinical practice of up-titrating DHEC and subsequently adapting L-Dopa to the individual needs of patients.

Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine.

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.

Single dose pharmacokinetics of alpha-dihydroergocryptine in patients with moderate to severe renal insufficiency.

AIM: This study was carried out to evaluate the pharmacokinetic profile of alpha-dihydroergocryptine (CAS 14271-05-7, DHEC, Almirid) in plasma and urine in patients with moderately to severely impaired renal function (creatinine clearance < 30 ml.min-1.1.73 m-2), following administration of single oral doses. METHODS: This was an open, nonrandomized trial. Seven patients with chronic renal disease and six healthy subjects received a single dose of 20 mg DHEC. Blood and urine samples were taken at specified intervals up to 72 h after dosing. Concentrations of unchanged DHEC were determined by radio-immunoassay (RIA) and concentrations of unchanged DHEC plus pooled metabolites by enzyme-immunoassay (EIA), respectively. RESULTS: In patients with impaired renal function, the mean Cmax and AUC(0-infinity) values for unchanged DHEC were 2.1 (95% confidence interval CI: 0.99 to 4.42) and 1.85 (95% CI: 0.72 to 4.77) times larger than in controls. The 24-h urinary excretion was only 0.3 (95% CI: 0.12 to 0.71) times that in healthy subjects. Similar findings were recorded for total DHEC plus metabolites. CONCLUSIONS: As treatment with DHEC is in general uptitrated starting with doses as low as 5 mg DHEC, which are then increased while accounting for individual effects both in terms of efficacy and tolerability, the observed range of effects of impaired renal function on DHEC's pharmacokinetics does not suggest the need to revise this policy, although lower end-doses are likely to be achieved.

Interaction of cytochrome P450 3A inhibitors with P-glycoprotein.

Many clinically important drug interactions occur due to inhibition of human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump P-glycoprotein (Pgp) can be an additional locus contributing to these drug interactions because there is overlap in drugs that are substrates for both proteins. We screened a number of CYP3A inhibitors (macrolide antibiotics, azole antifungals, and ergotpeptides) for their ability to interact with Pgp, compared with prototypical Pgp inhibitors. We used cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism was defined by interactions of the drugs with four cell lines (LLC-PK1, L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM assay and characterized for their inhibitor constant (K(i)) toward calcein-AM. The compounds were further defined for their ability to inhibit MDR1 by their effect on vinblastine accumulation into L-MDR1 cells. Representative compounds from each class of drugs were further tested as Pgp substrates, defined by the ability of human Pgp or mouse mdr1a/Pgp to transport them across a polarized kidney epithelial cell in vitro. These same compounds were administered radiolabeled in vivo to mdr1a (+/+) and (-/-) mice and the distribution of radioactivity compared. The results are summarized as follows: 1) Some drug interactions with Pgp were substrate- and/or assay-dependent. 2) Ergot alkaloids were identified as a class of MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species differences in the structure-activity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions.