Alteration of drug metabolism can have a major impact on drug therapy versus drug toxicity. We will determine if inhibition of the metabolism of 1-alpha-acetylmethadol (LAAM) will result in a decrease of its pharmacodynamic effect. LAAM is sequetially N- demethylated to the active metabolites norLAAM and dinorLAAM. Our preliminary data support the role of cytochrome P-450 3A4 (P450 3A4) in both of these reactions. P450 3A4 is inihibited by a number of medications including ketoconazole. The importance of norLAAM and dinorLAAM in the pharmacokinetics and pharmacodynamic efficts of LAAM are estblished. The following experiments will test our hypothesis that inihibition of LAAM metabolism will decrease its pharmacodynamic activity, as well as determine the mechanism for such an effect. Michaelis-Menten kinetics of LAAM and for LAAM N-demethylation will be determined in human liver microsomes to estimate their contribution to the intrinsic clearance (Vmax/Km) of LAAM and determine optimal substrate concentrations for subsequent experiments. The role of P450 3A4 in these reactions will then be confirmed by selective inhibition of the N-demethylations in human livermicrosomes, correlation of the inter-individual variation of these reactions with the variation in isozyme-selective activities in human liver microsomes, and determination of the rates of N- demethylation by cDNA-expressed human P450s. Our hypothesis will then be tested in humans given a single oral dose of LAAM with or without ketoconazole. We predict ketoconazole will increase the half-life of LAAM, decrease the productio of norLAAM and dinorLAAM and dimnish a pharmacodynamic endpoint, pupillary constriction. These in vitro and in vivo studies are important to establish the safety and efficacy of LAAM under conditions of potential drug interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA010100-01A2
Application #
2395838
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1997-08-01
Project End
1999-06-30
Budget Start
1997-08-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Masson, Carmen L; Rainey, Petrie M; Moody, David E et al. (2014) Effects of HCV seropositive status on buprenorphine pharmacokinetics in opioid-dependent individuals. Am J Addict 23:34-40
Fang, Wenfang B; Lofwall, Michelle R; Walsh, Sharon L et al. (2013) Determination of oxycodone, noroxycodone and oxymorphone by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in human matrices: in vivo and in vitro applications. J Anal Toxicol 37:337-44
Moody, David E (2013) Metabolic and toxicological considerations of the opioid replacement therapy and analgesic drugs: methadone and buprenorphine. Expert Opin Drug Metab Toxicol 9:675-97
Gruber, Valerie A; Rainey, Petrie M; Moody, David E et al. (2012) Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir. Clin Infect Dis 54:414-23
Chang, Yan; Fang, Wenfang B; Lin, Shen-Nan et al. (2011) Stereo-selective metabolism of methadone by human liver microsomes and cDNA-expressed cytochrome P450s: a reconciliation. Basic Clin Pharmacol Toxicol 108:55-62
Moody, David E; Fang, Wenfang B; Morrison, Jerdravee et al. (2011) Gender differences in pharmacokinetics of maintenance dosed buprenorphine. Drug Alcohol Depend 118:479-83
McCance-Katz, Elinore F; Moody, David E; Prathikanti, Sudha et al. (2011) Rifampin, but not rifabutin, may produce opiate withdrawal in buprenorphine-maintained patients. Drug Alcohol Depend 118:326-34
McCance-Katz, Elinore F; Moody, David E; Morse, Gene D et al. (2010) Lack of clinically significant drug interactions between nevirapine and buprenorphine. Am J Addict 19:30-7
McCance-Katz, Elinore F; Rainey, Petrie M; Moody, David E (2010) Effect of cocaine use on buprenorphine pharmacokinetics in humans. Am J Addict 19:38-46
Baker, Jennifer; Rainey, Petrie M; Moody, David E et al. (2010) Interactions between buprenorphine and antiretrovirals: nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine, lamivudine, and tenofovir. Am J Addict 19:17-29

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