Pharmacokinetic studies of a novel anticonvulsant, 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane, in rats.
The pharmacokinetic properties of 2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane (AAP-Cl) were studied in rats after intravenous and oral administration. The blood concentrations of AAP-Cl in rats showed a biexponential decline following intravenous administration of pharmacologic doses ranging from 10 to 100 mg/kg in rats. The terminal elimination half-lives (t((1/2)beta)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 5.80+/-0.30, 6.02+/-0.16 and 6.05+/-0.08 h, respectively. The total clearances (CL) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 1.29+/-1.10, 1.38+/-0.07 and 1.33+/-0.13l/(h kg), respectively. The apparent volumes of distribution at steady state (V(ss)) of AAP-Cl at the 10, 50 and 100 mg/kg dose levels were 7.96+/-0.51, 8.24+/-0.31 and 8.17+/-0.43l/kg, respectively. The AUC(0-infinity) increased proportionately to the intravenous bolus dose of AAP-Cl given (10-100 mg/kg). Statistical analysis of the t((1/2)beta), V(ss) and CL values for AAP-Cl between doses indicates that AAP-Cl exhibits dose-independent kinetics (P>0.05). AAP-Cl was absorbed rapidly after an oral dose of 100 mg/kg with peak concentrations (C(max)) in blood (3.5+/-0.33 microg/ml) reached after 30 min of drug administration. The oral bioavailability of AAP-Cl was 19.5+/-3.4% following administration of a single 100 mg/kg dose in rats. Urine analysis indicates that 2.5+/-0.45% of the administered dose of AAP-Cl (100 mg/kg, p.o.) is recovered unchanged in urine within 0-24 h. These findings may be useful in designing new aminoalkylpyridine anticonvulsants with improved efficacy and disposition profiles in animal models of epilepsy.
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Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140, USA. ivo.nnane@temple.edu
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D000284:Administration, Oral; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
C119418:2-(4-chlorophenyl)amino-2-(4-pyridyl)ethane; D000814:Aniline Compounds; D000927:Anticonvulsants; D011725:Pyridines