The metabolism in vitro and hepatic microsomal interactions of some enantiomeric drug substrates

• Published in: Biochemical journal 1970-05, Vol.117 (5), p.833-841
• Main Authors: Hewick, D S, Fouts, J R
• Format: Article
• Language: English
• Subjects: Amphetamine - metabolism; Animals; Appetite Depressants - metabolism; Benzphetamine - metabolism; Dextroamphetamine - metabolism; In Vitro Techniques; Kinetics; Male; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; NADP - metabolism; Oxidoreductases - analysis; Phenethylamines - metabolism; Propylamines - metabolism; Rabbits; Spectrum Analysis; Stereoisomerism
• ISSN: 0264-6021; 0306-3283; 1470-8728
• DOI: 10.1042/bj1170833

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.