Biomaterial Database

Pharmacokinetic analysis of the metabolism of cocaine to norcocaine and N-hydroxynorcocaine in mice. 1992

C S Boyer, and D R Petersen

School of Pharmacy, University of Colorado Health Sciences Center, Boulder.

Cocaine is hepatotoxic in humans and is a very effective hepatotoxin in the mouse. Previous in vitro studies have shown that the mixed function oxidase system is very important in the metabolism of cocaine to the hepatotoxic species. Activation of cocaine to the cytotoxic species is thought to proceed through the N-demethylation and subsequent N-hydroxylation of the bridgehead amine. The in vivo metabolism of cocaine involves not only oxidative but also hydrolytic mechanisms. Therefore the principle aim of this study was to establish a system in which the in vivo metabolism of cocaine to norcocaine and N-hydroxynorcocaine could be determined. The in vivo metabolism of acutely administered cocaine to norcocaine and N-hydroxynorcocaine was assessed in two inbred mouse strains; one that is relatively sensitive to cocaine hepatotoxicity but shows little enhancement in toxicity when pretreated with phenobarbital (DBA/2lbg), and one that shows little hepatotoxicity unless pretreated with phenobarbital (C57BL/6lbg). Although no significant differences between the strains were seen in the pharmacokinetics of cocaine, the half-life of both norcocaine and N-hydroxynorcocaine was significantly longer in DBA mice. Accordingly, the area under the curve values for hepatic norcocaine and N-hydroxynorcocaine were approximately 5- and 3-fold greater, respectively, in DBA as compared with C57BL mice. The higher levels of both norcocaine and N-hydroxynorcocaine in the DBA mouse are consistent with previously established differences in cocaine hepatotoxicity in these strains of mice. Pretreatment of C57BL mice with phenobarbital prolonged the half-life of norcocaine and N-hydroxynorcocaine 5- to 8-fold over C57BL control values.(ABSTRACT TRUNCATED AT 250 WORDS)

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D008810	Mice, Inbred C57BL	One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases.	Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008811	Mice, Inbred DBA	An inbred strain of mouse. Specific substrains are used in a variety of areas of BIOMEDICAL RESEARCH such as DBA/1J, which is used as a model for RHEUMATOID ARTHRITIS.	Mice, DBA,Mouse, DBA,Mouse, Inbred DBA,DBA Mice,DBA Mice, Inbred,DBA Mouse,DBA Mouse, Inbred,Inbred DBA Mice,Inbred DBA Mouse
D010634	Phenobarbital	A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations.	Phenemal,Phenobarbitone,Phenylbarbital,Gardenal,Hysteps,Luminal,Phenobarbital Sodium,Phenobarbital, Monosodium Salt,Phenylethylbarbituric Acid,Acid, Phenylethylbarbituric,Monosodium Salt Phenobarbital,Sodium, Phenobarbital
D003042	Cocaine	An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake.	Cocaine HCl,Cocaine Hydrochloride,HCl, Cocaine,Hydrochloride, Cocaine
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001711	Biotransformation	The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.
D013045	Species Specificity	The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species.	Species Specificities,Specificities, Species,Specificity, Species
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus