Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites.

OBJECTIVES: The multidrug transporter P-glycoprotein (P-gp) appears to play a significant role in drug absorption and disposition. Hence, it is of interest to evaluate structure-affinity relationships for the purpose of making predictions.
METHODS: The affinity to P-gp of related molecular structures from various groups of drugs was determined using competitive radioligand-binding assays. Structural analogs, stereoisomers and metabolites of verapamil-type calcium antagonists, beta-adrenoceptor antagonists as well as omeprazole, omeprazole enantiomers and the sulfone metabolite of omeprazole were investigated.
RESULTS: Whereas some stereoselectivity was detected for the high-affinity P-gp substrates verapamil and carvedilol, little or no differences were observed in the case of other beta-blockers. One of the 4 labetalol stereoisomers, the R,R-isomer dilevalol, had an IC50 value half that of labetalol.
CONCLUSIONS: Metabolites of verapamil, gallopamil, carvedilol and omeprazole are characterized by having higher IC50 values (lower P-gp affinity) than the respective parent compounds. Only the acebutolol metabolite, diacetolol, had a P-gp affinity comparable to that of the parent compound.