Plasma and urine, pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction

Objective: The aim of this study was to evaluate the pharmacokinetic behavi or of unchanged alpha -dihydroergocryptine (DHEC, Almirid (R), Desitin Arzn eimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg ) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and urin e in patients with impaired hepatic function, following administration of s ingle oral doses. Methods: The study was carried out according to an open, uncontrolled, parallel-group design, investigating two study groups: patien ts with hepatic dysfunction, i.e. with evidence of stable cirrhosis (n = 10 ) and age- and sex-matched healthy subjects (n = 8). Each subject received a single dose of 20 mig DHEC. Blood samples were taken at specified interva ls up to 72 h after dosing and urine was collected fractionally for 24 h. C oncentrations of unchanged DHEC were determined by RIA and concentrations o f total DHEC (unchanged and pooled metabolites) by EIA. Results: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterize d by large variability. In patients with impaired hepatic function, the geo metric mean C-max. and AUC(0-infinity) values for unchanged DHEC were 571.3 pg/ml (CV: 0.87) and 4038 pgxh/ml (CV: 1.04) and were approximately 2 time s (2.04, 95% CI: 0.93 to 4.46 and 2.11, 95% CI: 0.58 to 7.73 for C-max and AUC(0-infinity), respectively) larger than those measured in age-matched he althy controls. The 24-hour urinary excretion was approximately 3 times (3. 41, 95% CI: 0.95 to 12.21) higher in patients with hepatic dysfunction. Sim ilar results were obtained for total DHEC. Conclusions: The results reflect an increased systemic exposure in patients with impaired hepatic function which is not due to a reduced urinary excretion/elimination or reduced rena l clearance. The most likely mechanism involved is a reduction in pre-syste mic biotransformation. The observed range of effects on the pharmacokinetic s of DHEC in patients with compromized hepatic function does not suggest th e need to revise the dosage recommendations, since treatment with DHEC is g enerally started with low doses and is slowly up-titrated according to the individual response and the occurrence of adverse effects. Nevertheless, lo wer maintenance doses are likely to be achieved.