Buspar clinical pharmacology
The mechanism of action of Buspar is unknown. Buspar differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. In vitro preclinical studies have shown that Buspar has a high affinity for serotonin (5-HT1A) receptors. Buspar has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models.
Buspar has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that Buspar may have indirect effects on other neurotransmitter systems.
BuSpar is rapidly absorbed in man and undergoes extensive first-pass metabolism. In a radiolabeled study, unchanged Buspar in the plasma accounted for only about 1% of the radioactivity in the plasma. Following oral administration, plasma concentrations of unchanged Buspar are very low and variable between subjects. Peak plasma levels of 1 ng/mL to 6 ng/mL have been observed 40 to 90 minutes after single oral doses of 20 mg. The single-dose bioavailability of unchanged Buspar when taken as a tablet is on the average about 90% of an equivalent dose of solution, but there is large variability.
The effects of food upon the bioavailability of BuSpar have been studied in eight subjects. They were given a 20 mg dose with and without food; the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of unchanged Buspar increased by 84% and 116%, respectively, but the total amount of Buspar immunoreactive material did not change. This suggests that food may decrease the extent of presystemic clearance of Buspar.
A multiple-dose study conducted in 15 subjects suggests that Buspar has nonlinear pharmacokinetics. Thus, dose increases and repeated dosing may lead to somewhat higher blood levels of unchanged Buspar than would be predicted from results of single-dose studies.
An in vitro protein binding study indicated that approximately 86% of Buspar is bound to plasma proteins. It was also observed that aspirin increased the plasma levels of free Buspar by 23%, while flurazepam decreased the plasma levels of free Buspar by 20%. However, it is not known whether these drugs cause similar effects on plasma levels of free Buspar in vivo, or whether such changes, if they do occur, cause clinically significant differences in treatment outcome. An in vitro study indicated that Buspar did not displace highly protein-bound drugs such as phenytoin, warfarin, and propranolol from plasma protein, and that Buspar may displace digoxin.
Buspar is metabolized primarily by oxidation, which in vitro has been shown to be mediated by cytochrome P450 3A4 (CYP3A4). Several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP), are produced. In animal models predictive of anxiolytic potential, 1-PP has about one quarter of the activity of Buspar, but is present in up to 20-fold greater amounts. However, this is probably not important in humans: blood samples from humans chronically exposed to BuSpar (Buspar hydrochloride) do not exhibit high levels of 1-PP; mean values are approximately 3 ng/mL and the highest human blood level recorded among 108 chronically dosed patients was 17 ng/mL, less than 1/200th of 1-PP levels found in animals given large doses of Buspar without signs of toxicity.
In a single-dose study using 14C-labeled Buspar, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose. The average elimination half-life of unchanged Buspar after single doses of 10 mg to 40 mg is about 2 to 3 hours.
Buspar in Special Populations
Buspar and Age and Gender Effects
After single or multiple doses in adults, no significant differences in Buspar pharmacokinetics (AUC and Cmax) were observed between elderly and younger subjects or between men and women.
Buspar and Hepatic Impairment
After multiple-dose administration of Buspar to patients with hepatic impairment, steady-state AUC of Buspar increased 13-fold compared with healthy subjects.
Buspar and Renal Impairment
After multiple-dose administration of Buspar to renally impaired (Clcr = 10–70 mL/min/1.73 m2) patients, steady-state AUC of Buspar increased 4-fold compared with healthy (Clcr≥80 mL/min/1.73 m2) subjects.
Buspar Race Effects
The effects of race on the pharmacokinetics of Buspar have not been studied.
