Chemical formula: C₉H₉Cl₂N₃O Molecular mass: 246.093 g/mol PubChem compound: 3519
Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a non-stimulant. The mode of action of guanfacine in ADHD is not fully established. Preclinical research suggests guanfacine modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic noradrenalin transmission at the alpha2-adrenergic receptors.
Guanfacine is a known antihypertensive agent. By stimulating alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor centre to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and blood pressure, and a reduction in heart rate.
Guanfacine is readily absorbed, with peak plasma concentrations reached approximately 5 hours after oral administration in paediatric patients (children and adolescents 6-17 years old inclusive). In adults, the mean exposure of guanfacine increased (Cmax ~75% and AUC ~40%) when it was taken together with a high fat meal, compared to intake in the fasted state.
Guanfacine is moderately bound to plasma proteins (approximately 70%), independent of drug concentration.
Guanfacine is metabolised via CYP3A4/5-mediated oxidation, with subsequent phase II reactions of sulphation and glucuronidation. The major circulating metabolite is 3-OH-guanfacine sulphate which lacks pharmacological activity.
Guanfacine is a substrate of CYP3A4 and CYP3A5, and exposure is affected by CYP3A4 and CYP3A5 inducers and inhibitors. In human hepatic microsomes, guanfacine did not inhibit the activities of the other major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5); guanfacine is also not expected to be an inducer of CYP3A, CYP1A2 and CYP2B6.
Based on in vitro studies, guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 or MATE2. Guanfacine is not an inhibitor of BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or MATE2K, but it is an inhibitor of MATE1 and may be an inhibitor of OCT1 at maximal portal vein concentrations.
Guanfacine is cleared by the kidneys via filtration and active secretion and the liver. Active renal secretion is mediated via OCT2 transporter. Renal excretion is the major elimination pathway (80%) with parent drug accounting for 30% of the urinary radioactivity. The major urinary metabolites were 3-hydroxy guanfacine glucuronide, guanfacine dihydrodiol, 3-hydroxy guanfacine sulphate. The elimination half-life of guanfacine is approximately 18 hours.
The pharmacokinetics of guanfacine is similar in children (aged 6 to 12) and adolescents (aged 13 to 17) ADHD patients, and healthy adult volunteers.
There have been no studies performed in children with ADHD under the age of 6 years with guanfacine.
Systemic exposure to guanfacine is similar for men and women given the same mg/kg dose.
Formal pharmacokinetic studies for race have not been conducted. There is no evidence of any impact of ethnicity on the pharmacokinetics of guanfacine.
No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice at doses up to 10 mg/kg/day. A significant increase in incidence of adenomas of the pancreatic islet was observed in male rats treated with 5 mg/kg/day guanfacine for 102 weeks but not in female rats. The clinical relevance is unknown.
Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test.
General toxicity observed in animals (rat, dog) upon treatment with guanfacine included prolongation of uncorrected QT interval (heart), atrophic spleen and decreased white blood cells, affected liver – increased bilirubin and ALT levels included, irritated and inflamed intestines, increased creatinine and blood urea nitrogen levels (kidney), corneal clouding (eye) in rat and mouse only, alveolar macrophage infiltration & pneumonitis and reduced spermatogenesis.
No adverse effects were observed in a fertility study in female rats at doses up to 22 times the maximum recommended human dose on a mg/m² basis.
Male fertility was affected at 8 mg/kg/day, the lowest dose tested, equivalent of 10.8 times the maximum recommended human dose of 0.12 mg/kg on a mg/m² basis. Due to lack of proper toxicokinetic data, comparison to human clinical exposure was not possible.
Guanfacine showed embryo foetal developmental toxicity in mice and rats (NOAEL 0.5 mg/kg/day) and in rabbits (NOAEL 3.0 mg/kg/day) in the presence of maternal toxicity. Due to a lack of proper toxicokinetic data, comparison to human clinical exposure was not possible.
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