Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites.
OBJECTIVE
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.
Neuhoff
S
S
School of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
Langguth
P
P
Dressler
C
C
Andersson
T B
TB
Regårdh
C G
CG
Spahn-Langguth
H
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001667:Binding, Competitive; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009853:Omeprazole / Q000031:analogs & derivatives / Q000378:metabolism*; D011869:Radioligand Assay; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism*; D014747:Vinblastine / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000319:Adrenergic beta-Antagonists; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D014747:Vinblastine; D014700:Verapamil; D009853:Omeprazole