title: A new radioligand binding assay for cytochrome P450IID1 (CYP2D1) in rat liver microsomes: a tool to predict sparteine/debrisoquine type polymorphism of drugs.
abstract: [3H]-Mepyramine ([3H]-pyrilamine) has a high affinity for cytochrome P450IID1 (CYP2D1) in rat liver microsomes, the isoenzyme involved in the oxidative metabolism of debrisoquine. Drugs known to interact with this enzyme, as either substrate or inhibitor, displaced [3H]-mepyramine. Compounds specific for other P450 isoenzymes did not displace [3H]-mepyramine. Drugs that are positive in this binding assay can be either substrates or inhibitors of CYP2D1 and warrant further research to investigate possible polymorphism. Substrates could reach toxicological concentrations, and inhibitors can have drug interactions with known CYP2D6 substrates. Although care should be taken in the extrapolation from rat to human, since CYP2D1 and CYP2D6 have clear differences, this rapid, easy-to-perform and inexpensive assay has predictive value for the sparteine/debrisoquine type of polymorphic behavior of compounds and could be used at an early stage in drug development.
authors.affiliation: Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: H P
authors.initials: HP
authors.lastname: Voss
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: D
authors.initials: D
authors.lastname: Donnell
authors.forename: A
authors.initials: A
authors.lastname: Bast
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011738:Pyrilamine / Q000378:metabolism*; D011869:Radioligand Assay / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011738:Pyrilamine