Intravenous and oral clozapine pharmacokinetics, pharmacodynamics, and concentration-effect relations: acute tolerance.
We examined the pharmacokinetics and pharmacodynamics of intravenous (1-5 mg/kg) and oral clozapine (2.5-10 mg/kg) in rats (terminal half-life=81.8 min; oral bioavailability=5.32%). Both dose- and concentration-effect relations of clozapine were characterized. Clozapine's effects were similar to those of benzodiazepines because of the similarity in effect-time profiles between the two classes of drugs. The IC(50) value increased as a function of dose; consequently, clozapine's relative potency decreased linearly with the logarithm of AUC((0-infinity)), or bioavailable dose regardless of route of administration. The IC(50) is an index for the sensitivity of behavioral performance to clozapine; relative potency provides an index for estimating the extent of acute tolerance. As IC(50) increases, relative potency decreases, and consequently, acute tolerance increases. Our results demonstrated that greater acute tolerance was observed for i.v. clozapine than for p.o. clozapine; however, clozapine exhibited a single concentration-effect relation across dose and route of administration after correcting for relative potencies.
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Department of Chemistry, Rutgers, The State University of New Jersey (L.S.), 152 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
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D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D013997:Time Factors
D014150:Antipsychotic Agents; D003024:Clozapine