The overall goal of this proposal is to elucidate both the causes and effects of cannabinoid exposure on the biodistribution and metabolism of other drugs. A major aim will be to more fully characterize how cannabidiol (CBD)-pretreatment increases brain levels of other drugs of abuse and to determine the pharmacological consequences of those increases. CBD pretreatment not only markedly increases concentrations of tetrahydrocannabinol (THC) and its metabolites and metabolite half-times in the brain, but also increase the duration of THC-induced catalepsy. CBD pretreatment also increases brain levels of cocaine as well as acute cocaine-induced seizure activity and mortality. We will therefore determine the effect of CBD or THC pretreatment on brain levels of other drugs of abuse and its pharmacological consequences, as well as examine the effect of CBD or THC pretreatment on plasma protein binding, blood-brain barrier permeability, and circulating cytokines in order to characterize possible mechanisms contributing to the increased brain levels. Understanding the mechanisms involved in these alterations in brain pharmacokinetics is not only toxicologically important because marijuana is often coingested with many other drugs of abuse and clinically important drugs but could also prove advantageous, permitting increased entry into the CNS of specific pharmacological agents. Another specific objective includes an extension of our studies on the CBD-mediated modification of mouse P450 3A, by examining the effect of CBD on human P450 3A4. We therefore propose to isolate and characterize the CBD-modified peptide of human P450 3A4, as we have done for mouse P450 3A. Identification of the amino acid residue that is modified by CBD would increase our understanding of the active site of this clinically important P450, since direct x- ray crystallographic structural information of the enzyme active site is currently unavailable for this or any other mammalian P450. Site- directed mutagenesis studies will confirm the importance of this residue in catalytic function and in CBD-modification. Finally, we will determine the contribution of specific P450 subpopulations to the metabolism of cocaine in order to elucidate the mechanisms by which P450 bioactivates cocaine as well as to understand how CBD pretreatment protects against cocaine-induced liver damage. Our recent findings not only suggest that a presently unidentified P450(s) may contribute to cocaine bioactivation, but that it may also be susceptible to CBD-mediated inactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004265-14
Application #
6175153
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
1987-01-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2002-06-30
Support Year
14
Fiscal Year
2000
Total Cost
$190,092
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Reid, M J; Bornheim, L M (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61:1357-67
Reid, M J; Bornheim, L M (2001) The effects of phencyclidine pretreatment on cocaine-mediated hepatotoxicity in mice. Toxicol Appl Pharmacol 172:194-202
Bornheim, L M (2000) Effects of unsaturated side-chain analogs of tetrahydrocannabinol on cytochromes P450. Biochem Pharmacol 60:955-61
Jager, W; Correia, M A; Bornheim, L M et al. (1999) Ethynylestradiol-mediated induction of hepatic CYP3A9 in female rats: implication for cyclosporine metabolism. Drug Metab Dispos 27:1505-11
He, K; Bornheim, L M; Falick, A M et al. (1998) Identification of the heme-modified peptides from cumene hydroperoxide-inactivated cytochrome P450 3A4. Biochemistry 37:17448-57
Bornheim, L M (1998) Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity. Toxicol Appl Pharmacol 150:158-65
Bornheim, L M; Grillo, M P (1998) Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem Res Toxicol 11:1209-16
Kim, K Y; Bornheim, L M (1997) Determination of esterase-catalyzed cocaine metabolite formation by high-performance liquid chromatography with ultraviolet detection. J Chromatogr Sci 35:287-90
Jaeger, W; Benet, L Z; Bornheim, L M (1996) Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica 26:275-84
Bornheim, L M; Kim, K Y; Li, J et al. (1995) Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 23:825-31

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