Pharmacokinetics and metabolism of guanfacine in man

摘要

>1 The fate of guanfacine has been investigated extensively in animals.>2 Pharmacokinetics and metabolism of [¹⁴C]-guanfacine were studied in fourteen subjects given 3 mg orally (seven subjects) and 2.3 mg intravenously. Plasma levels and urinary excretion of radioactivity were measured by liquid scintillation counting. Parent drug was determined by gas chromatography-mass spectrometry. The analytical results were submitted to pharmacokinetic evaluation using the SAAM 26 programme. Metabolites in urine were identified by high pressure liquid chromatography.>3 Guanfacine was rapidly and completely absorbed. Its absolute bioavailability was close to 100%, no evidence of any first-pass effect being found.>4 Its distribution was characterized by low blood levels, low plasma protein binding and a relatively high affinity to the tissues (Vd of 300 l).>5 The elimination half-life of the β-phase was 17 hours. The major route of excretion (80% of the dose) was in the urine. About 1/3 to 1/4 of the total clearance of 11 l/h was renal.>6 The principal metabolite was the 3-hydroxy-derivative of guanfacine conjugated as either O-glucuronide or O-sulphate. The important fraction (30%) of parent drug found in the urine demonstrates a rather moderate biotransformation of guanfacine in man.>7 The results of an additional study after multiple dosing showed that the measured steady-state plasma levels were in agreement with the values predicted from a single dose experiment and proportional to the daily dosage.