PT  - JOURNAL ARTICLE
AU  - Nims, R W
AU  - McClain, R M
AU  - Manchand, P S
AU  - Belica, P S
AU  - Thomas, P E
AU  - Mellini, D W
AU  - Utermahlen, W E
AU  - Lubet, R A
TI  - Comparative pharmacodynamics of hepatic cytochrome P450 2B induction by 5,5-diphenyl- and 5,5-diethyl-substituted barbiturates and hydantoins in the male F344/NCr rat.
DP  - 1994 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 348--355
VI  - 270
IP  - 1
4099  - http://jpet.aspetjournals.org/content/270/1/348.short
4100  - http://jpet.aspetjournals.org/content/270/1/348.full
SO  - J Pharmacol Exp Ther1994 Jul 01; 270
AB  - To explore further the structural requirements for ligand interaction with the putative phenobarbital receptor, the pharmacodynamics of CYP2B induction by 5,5-diphenylbarbituric acid, phenytoin (5,5-diphenylhydantoin), barbital (5,5-diethylbarbituric acid) and 5,5-diethylhydantoin were investigated in the male F344/NCr rat. Steady-state total (free plus protein-bound) serum drug concentration, measured after 14 days of administration of the compounds in the diet, was used as an approximation of intrahepatocellular drug concentration. The serum concentrations associated with half-maximal hepatic CYP2B induction (EC50 values) were 6 to 11 microM and 15 to 18 microM for the diphenyl-substituted barbiturate and hydantoin, respectively, based on measurement of pentoxy- or benzyloxyresorufin O-dealkylation activities, or immunoreactive CYP2B1 protein. The corresponding potency values for the diethyl-substituted barbiturate and hydantoin were 16 to 20 microM and > or = 500 microM, respectively. The magnitudes of the maximal CYP2B induction responses elicited by the diphenyl-substituted congeners and by barbital were 94 to 122% of the responses resulting from phenobarbital itself. In contrast, the maximum induction responses elicited by 5,5-diethylhydantoin were only 24% as great as those elicited by phenobarbital. The finding of a CYP2B inducer with a potency value 2 to 3 orders of magnitude lower than those for certain other prototype CYP2B inducers is suggestive but not proof of receptor mediation in the induction process.