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.
Nims
R W
RW
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland.
McClain
R M
RM
Manchand
P S
PS
Belica
P S
PS
Thomas
P E
PE
Mellini
D W
DW
Utermahlen
W E
WE
Lubet
R A
RA
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