Buspirone (BP), a newly developed antianxiety agent, forms 1-(2-pyrimidinyl)-piperazine (PmP) during its biotransformation in rats and man. After oral administration of pharmacologically effective doses of BP-hydrochloride to rats (1 and 10 mg/kg), the metabolite appears in significant amounts in body fluids and tissues; it is highly concentrated in the central nervous system, the brain-to-plasma concentration ratios being approximately 5 at the time of the maximum concentrations (Cmax). In man given the anxiolytic dose (20 mg) of BP the metabolite reaches higher plasma Cmax values than its parent drug. Its plasma elimination t1/2 is more than double that for BP. These results, together with the fact that PmP is biochemically and pharmacologically active, suggest that the metabolite may contribute significantly to the central effects of the parent drug.
The presence of an imidazole moiety in the chemical structure of denzimol and nafimidone suggested that these new anticonvulsants might interfere with cytochrome P450-mediated mixed function monooxygenase activities. We therefore investigated their ability to bind reversibly to rat liver cytochrome P450. Both drugs displayed a type II spectra. The Ks values of binding were 6.66 and 7.00 mM, respectively, for denzimol and nafimidone. In other in-vitro studies the IC50 of the inhibition caused by denzimol and nafimidone was determined on carbamazepine (CBZ) epoxidation and diazepam C3-hydroxylation and N1-dealkylation. The IC50 values for CBZ epoxidation were 4.46 x 10(-7) and 2.95 x 10(-7) M, respectively, in the presence of denzimol and nafimidone. The IC50 values for diazepam C3-hydroxylation were 1.44 x 10(-6) and 1.00 x 10(-6) M, respectively, and those for N1-dealkylation 6.66 x 10(-7) and 5.95 x 10(-7) M. The inhibition of CBZ metabolism was also investigated ex-vivo and in-vivo after single oral doses (15 and/or 60 mg kg-1) of denzimol or nafimidone. Inhibition of CBZ-10,11-epoxidation by the two drugs was time- and dose-dependent. Further studies in-vivo showed that denzimol and nafimidone prolong pentobarbitone sleeping times indicating that both drugs bind to rat liver microsomes and are potent inhibitors in the rat of mixed function monooxygense activities both in-vitro and in-vivo.
The analgesic antrafenine forms 1-m-trifluoromethylphenylpiperazine (mCF3PP) during its biotransformation in the rat and mouse. At least 14 and 3% of an antrafenine dose (25 mg kg-1 p.o.) reaches the systemic circulation as mCF3PP in the mouse and rat respectively. The metabolite easily enters the brain, reaching concentrations several times those in body fluids. This, together with the fact that mCF3PP is known to produce several pharmacological effects compatible with a stimulatory action on 5-hydroxytryptamine postsynaptic receptors, suggests that this metabolite may contribute to the parent drug's pharmacological effects.
The disposition of eight 1-aryl-piperazines was investigated in rats after i.v. administration. The concentration of 1-aryl-piperazine in body fluids and tissues was determined by h.p.l.c. or electron-capture g.l.c. Correlations of kinetics and physiological parameters with the lipophilicity of each 1-aryl-piperazine, determined by h.p.l.c. retention on a reverse-phase C18 column at neutral pH, were investigated. Binding to rat plasma proteins varied within the series, increasing with lipophilicity. For the majority of the derivatives the blood-to-plasma ratio was close to unity, implying an almost equal distribution between erythrocytes and plasma. The most lipophilic 1-aryl-piperazine of the series partitioned more into erythrocytes. The eight compounds differed widely in Vss and total Cl values and as a general trend both values increased with lipophilicity. The percentage of the dose excreted unchanged in the urine decreased progressively with increasing lipophilicity. 1-Aryl-piperazines were distributed extensively in all the tissues examined, concentrating particularly in the eliminating organs and lung. They easily entered the rat brain, Cmax values generally being reached within five minutes of parenteral injection. 1-Aryl-piperazine brain uptake increased with lipophilicity.
In vivo and in vitro alterations in carbamazepine (CBZ) metabolism and the extent of enzyme induction of the hepatic cytochrome P-450 system after chronic oral denzimol to rats were evaluated. No effect on drug-metabolizing enzymes was detected for this new anticonvulsant drug at a dose of 15 mg/kg, which is just above the anticonvulsive dose. At higher doses (60 mg/kg) denzimol significantly raised the hepatic cytochrome P-450 content, enhanced CBZ clearance and tend to shorten its elimination t½ and that of its active metabolite. These results, combined with those of a previous study showing impairment of CBZ metabolism after single doses of denzimol, suggest that the drug may have either inductive or inhibitory effects on microsomal mixed-function oxidase activity in the rat, depending on the dose and schedule of treatment.
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