Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients.
Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.
Kurzawski
Mateusz
M
Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstańców Wlkp. 72, PL 70-111 Szczecin, Poland.
Bartnicka
Lilianna
L
Florczak
Marcin
M
Górnik
Wanda
W
Droździk
Marek
M
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D004247:DNA / Q000032:analysis; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008520:Medigoxin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D004077:Digoxin; D004247:DNA; D008520:Medigoxin