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.
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.
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland.
R W
RW
Nims
R M
RM
McClain
P S
PS
Manchand
P S
PS
Belica
P E
PE
Thomas
D W
DW
Mellini
W E
WE
Utermahlen
R A
RA
Lubet
D000478:Alkylation; D000818:Animals; D001462:Barbital / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006827:Hydantoins / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010078:Oxazines / Q000378:metabolism; D010634:Phenobarbital / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D006827:Hydantoins; D010078:Oxazines; C044127:5,5-diphenylbarbituric acid; C055540:5,5-diethylhydantoin; D001462:Barbital; D010672:Phenytoin; C057754:benzyloxyresorufin; C044943:pentoxyresorufin; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital