Pharmacokinetics and metabolism of guanfacine in man: a review.

Abstract

IThe 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 1).5 The elimination half-life of the f-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 11I/h was renal. 6 The principal metabolite was the 3-hydroxy-derivative of guanfacine conjugated as either 0-glucuronide or 0-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.

Comparison of the Actions of Centrally and Peripherally Administered Clonidine and Guanfacine in the Rabbit: Investigation of the Differences

“…Kiechel (1980) reports a plasma terminal half life of 17 h in man for guanfacine, which may reflect this. Its levels in the brain are approximately the same after 15 min when the animal is hypertensive, at 90 min when it is normotensive, and at 180 min when it is hypotensive; however, the pressor effect gradually fades as the plasma concentration falls.…”

Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder

“…33,49,51,52 Indeed, as reported in an open-label dose-escalation pharmacokinetic evaluation, 40 with equal doses of GXR, observed guanfacine plasma concentrations were higher in children than in adolescents and adults, presumably due to the lower body weight of children. 42 Doses above 4 mg/day in children (aged 6-12 years) and above 7 mg/day in adolescents (aged 13-17 years) have not been studied. Likewise, doses above 54,55 as well as adjunctive pharmacotherapy in combination with stimulants for those patients who failed to have an adequate response with the latter medication.…”

“…40 Guanfacine is metabolized by oxidation to form 3-hydroxyguanfacine, its main metabolite. 42 As evidenced in an in vitro study assessing P-glycoprotein substrate properties, it appears that the role of P-glycoprotein in guanfacine transport is at best minor and unlikely to be of clinical relevance in interindividual variability in response to guanfacine therapy. 44 The cytochrome P450 (CYP)-3A4 isoenzyme is the primary enzyme involved in the oxidative metabolism of guanfacine.…”

“…33 Guanfacine is moderately bound to plasma protein, with 64%-72% bound to plasma proteins, independent of drug concentration. 42 Guanfacine is cleared both by the liver and the kidney. GXR has a long elimination half-life: 14.4 hours in children and 17.9 hours adolescents after a single 2 mg dose.…”

“…33,40 GXR is readily absorbed following oral administration, and has linear pharmacokinetics after administration of single 2 mg doses and repeated 2 mg and 4 mg doses in children and adolescents with ADHD. 27,40,41 While immediate-release guanfacine (GIR) has an oral bioavailability of approximately 80%, 42 the bioavailability of GXR is 58%. 22,33 Furthermore, compared with GIR, GXR was associated with a 60% reduction in peak plasma concentration (C max ) and a 43% reduction in area under the plasma concentration-time curve (AUC).…”