It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone. Chemistry
Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain. Analogues
Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone. Synthesis
Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).
In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine. Interactions
Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:
Itraconazole: Increased plasma level of buspirone
Rifampicin: Decreased plasma levels of buspirone
Nefazodone: Increased plasma levels of buspirone
Haloperidol: Increased plasma levels of buspirone
Carbamazepine: Decreased plasma levels of buspirone
Grapefruit: Significantly increases the plasma levels of buspirone. See grapefruit–drug interactions. Fluvoxamine: Moderately increase plasma levels of buspirone.Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs). Pharmacology
Pharmacodynamics
Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors. It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.