Cytochrome buspirone metabolism

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

Only phenobarbital strongly induces the synthesis of the hepatic cytochrome P-450 drug metabolizing system. Phenobarbital is contraindicated in the treatment of acute intermittent porphyria. Buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation, v ... 

GRAPEFRUIT JUICE BUSPIRONE ORAL Significant T pharmacodynamic effects. AUC T 9.2-fold and maximum concentration 4.3-fold, with t in T max. Possibly t efficacy and t adverse effects, e.g. sedation, CNS depression Possibly t bioavailability i presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited Avoid concomitant use. Be particularly vigilant in elderly patients or those with impaired liver function. Consider an alternative, e.g. temazepam... 

Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka J. Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab Dispos 2005a 33 500-507. 

Zaleplon, zolpidem and zopiclone are metabolised by several cytochrome CYP450 isoenzymes and it has been suggested that because of this, other drugs which affect a particular isoenzyme such as CYP3A4, may have less effect on their metabolism. However, their pharmacokinetics are affected by potent inducers such as rifampicin and by inhibitors such as the azole antifungals. Buspirone undergoes CYP3A4-mediated metabolism in the liver. 

The increased buspirone levels are thought to occur because both diltiazem and verapamil inhibit the cytochrome P450 isoenzyme CYP3A4, which is concerned with the metabolism of the buspirone. ... 

Not fully established, but it is almost certain that rifampicin induces the cytochrome P450 isoenzyme CYP3A4 in the gut and liver, which metabolises buspirone. Therefore the metabolism and clearance of buspirone are increased. 

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