The metabolism in vitro and hepatic microsomal interactions of some enantiomeric drug substrates.
1. The metabolism in vitro and microsomal interactions of (+)-amphetamine, (-)-amphetamine, (+)-benzphetamine and (-)-benzphetamine were studied with hepatic microsomes from phenobarbitone-pretreated male rabbits. 2. (+)-Benzphetamine was N-demethylated 30-35% faster than (-)-benzphetamine, but the apparent Michaelis constants for the two enantiomers were similar. 3. (-)-Amphetamine was deaminated about 200% faster than (+)-amphetamine. 4. The benzphetamine enantiomers gave qualitatively and quantitatively identical type I microsomal difference spectra (peak, 390nm; trough, 425nm) indicating identical apparent binding affinities for microsomes and identical spectral changes at maxima (DeltaE(max.) values). 5. The amphetamine enantiomers gave qualitatively identical type II microsomal difference spectra (peak, 433nm; trough, 395nm). However, the type II spectral data indicated that (+)-amphetamine had a markedly higher apparent binding affinity than (-)-amphetamine for microsomes. The amphetamine enantiomers gave identical DeltaE(max.) values. 6. The benzphetamine enantiomers (0.5mm) enhanced the rate of microsomal cytochrome P-450 reduction by NADPH by 400-500%, (+)-benzphetamine enhancing the rate 20-25% more than (-)-benzphetamine. 7. The amphetamine enantiomers decreased the rate of microsomal cytochrome P-450 reduction by NADPH. At a concentration of 2mm, (+)-amphetamine decreased the rate more than (-)-amphetamine. 7. All four enantiomers enhanced microsomal NADPH oxidation.
D000661:Amphetamine / Q000378:metabolism*; D000818:Animals; D001067:Appetite Depressants / Q000378:metabolism*; D001589:Benzphetamine / Q000378:metabolism; D003913:Dextroamphetamine / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010088:Oxidoreductases / Q000032:analysis; D010627:Phenethylamines / Q000378:metabolism*; D011437:Propylamines / Q000378:metabolism*; D011817:Rabbits; D013057:Spectrum Analysis; D013237:Stereoisomerism
D001067:Appetite Depressants; D010627:Phenethylamines; D011437:Propylamines; D001589:Benzphetamine; D009249:NADP; D000661:Amphetamine; D010088:Oxidoreductases; D003913:Dextroamphetamine