Pharmacokinetic and Metabolism Study in Healthy Volunteers After Administration of Single Oral Dose of (3)H-alpha-Dihydroergocryptine Mesylate.
This phase I open pharmacokinetic and metabolism study was conducted with six healthy male volunteers who were given 20 mg of (3)H-alpha-dihydroergocryptine in order to evaluate the absorption, plasma time course, and urinary and fecal elimination of total radioactivity. Rapid absorption into the general circulation occurred with an average K(01) of 0.99 plus minus 0.73/h. Peak time(T(max)) was reached in approximately 3 h with an average radioactivity concentration (C(max)) of 8.78 plus minus 5.9 ng eq h/ml. Distribution from the central compartment to the peripheral compartment occurred with a mean rate constant (K(12)) of 0.330 plus minus 0.22/h. Estimations of total clearance (CL) and volume of distribution (Vd) seem strongly affected by the low oral availability (F) of hydrogenated ergots. The rate constant (K(21)) of radioactivity washout from the tissue to the central compartment was 0.250 plus minus 0.130/h. However, plasma radioactivity declined biexponentially with an overall elimination constant (K(10)) of 0.029 to 0.146/h (i.e, half-lives of 23.9--4.75/h). Total radioactivity recovery in urine and feces was good with 82.78 plus minus 6.44% of dose eliminated in feces and 3.01 plus minus 0.65% in urine. The latter concentration was too low to detect metabolites or unchanged drug by radioactivity image scanning. However, the liquid scintillation count of silica gel that had been scraped off the thin layer chromatography (TLC) plates indicated the presence of metabolites in urine. Pharmacodynamically, both supine and standing blood pressure fell significantly within the first 8 h of dosing, yet there were no changes in heart rate. No adverse reactions were reported. In conclusion, the kinetics of (3)H-dihydroergocryptine are very similar to other ergot alkaloids in respect to extensive hepatic metabolism with an elimination half-life of 25 h.
Ronca
F.
F
Institute of Biological Chemistry, University of Pisa, Pisa, Italy.
Guazzelli
M.
M
Salvadori
P.
P
Palumbo
R.
R
Neuteboom
B.
B
Ambrosoli
L.
L
Poli
A.
A
Girardello
R.
R
Lowenthal
D. T.
DT