Buspirone metabolism

Louilot, A., Le Moal, M., and Simon, H., Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry, Life Sci., 40, 2017, 1987. 

Pharmacokinetics Buspirone is rapidly absorbed and undergoes extensive first-pass metabolism. Approximately 95% of buspirone is plasma protein bound. In a single dose study, 29% to 63% of the dose was excreted in the urine within 24 hours. 

Renal/Hepatic function Impairment Because buspirone is metabolized by the liver and excreted by the kidneys, do not use in patients with severe hepatic or renal impairment. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Furthermore, as already discussed, important ethnic variations exist in the metabolic activity of both CYP3A4 and 2D6 and caution is needed when administering buspirone to Asians who are more likely to be slow metabolizers of CYP2D6 substrates and may also be on other medications that further inhibit CYP2D6 activity. 

Buspirone is well absorbed from the gastrointestinal tract, and peak blood levels are achieved in 1 to 1.5 hours the drug is more than 95% bound to plasma proteins. Buspirone is extensively metabolized, with less than 1% of the parent drug excreted into the urine unchanged. At least one of the metabolic products of buspirone is biologically active. The parent drug has an elimination half-life of 4 to 6 hours. 

The half-life of Buspirone in healthy volunteers is 1 to 11 hours (Cole and Yonkers, 1995 Chouinard et ah, 1999). Buspirone is metabolized mainly by hydrox-ylation to 6 OH-buspirone and by N-dealkylation to 1-pyrimidinylpiperaxine (1-PP) (Jajoo et ah, 1989). There are at least seven major and five minor metabolites (Jajoo et ah, 1989 Chouinard et ah, 1999). 

Metabolism and clearance of buspirone is decreased with hepatic cirrhosis and renal disease (Gammans et ah, 1986). 

Chouinard, G., Lefko-Singh, K., and Teboul, E. (1999) Metabolism of anxiolytics and hypnotics benzodiazepines, buspirone, zopli-cone, and zolpidem. Cell Mol Neurobiol 19 533—552. 

Jajoo, H.K., Mayol, R.R, Labudde, J.A., and Blair, LA. (1989) Metabolism of the antianxiety drug buspirone in human subjects. Drug Metab Dispos 17 634-640. 

Finally, while on the subject of possible clinical effects of (%2 antagonism, it should be noted that many of the 5-HT, agonists (e.g., buspirone, gepirone, and ipsapirone] that were developed or tested for antianxiety and antidepressant effects are extensively metabolized to l-(2-pyrimidyl]-piperazine, itself an active 0(2-adrenoceptor antagonist (G. Bianchi et al. 1988). Whether this is relevant in vivo in humans remains to be seen. 

Buspirone is metabolized by CYP 3A3/4. Therefore, the initial dose should be lower in patients who are also taking medications known to inhibit these enzymes, such as nefazodone. 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

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. 

Figure 5.6 Structure of buspirone with areas susceptible to metabolic or chemical degradation highlighted for rapid visualization of the soft spots of the structure. (Courtesy of Milestone Development Services, Newtown, Pa., USA.)...

Table 6.11 illustrates a representative buspirone metabolite structure database. Information on the structure, molecular weight, UV characteristics, RRT, and product ions of metabolites obtained from rat bile, urine, and liver S9 samples are compiled. Using this format, the predominant buspirone metabolite profile groups, As-B-P, A-B-Ps, and As-B-Ps are easily recognized. These profile groups indicate azaspirone decane dione and pyrimidine as metabolically active sites of attack and the presence of multiple substitution sites on each of these substructures. In many cases, the profile groups indicate the occurrence of metabolic reactions on more than one substructure. 

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 ... 

Antibiotics (erythromycin, chloramphenicol, isoniazid) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39) (SEDA-22, 41). 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

CALCIUM CHANNEL BLOCKERS BUSPIRONE Plasma concentrations of buspirone are t by diltiazem and verapamil Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of buspirone Start buspirone at a lower dose (2.5 mg twice daily suggested by the manufacturers) in patients on calcium channel blockers... 

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