ABCMdb

PMID: 16415525

Sakaeda T
MDR1 genotype-related pharmacokinetics: fact or fiction?
Drug Metab Pharmacokinet. 2005 Dec;20(6):391-414., [PubMed]

Sentences

No. Mutations Sentence Comment

27 ABCB1 p.Gly185Val In 1989, the ˆrst report on the polymorphisms of the MDR1 gene was presented by Kioka et al.30) Two amino acid substitutions, Gly185Val and Ala893Ser, were detected in MDR1 isolated from normal human adrenal glands, and the latter was suggested to re‰ect a genetic polymorphism. Login to comment 29 ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Asn21Asp ABCB1 p.Gln1107Pro ABCB1 p.Phe103Leu ABCB1 p.Ala999Thr ABCB1 p.Ser1141Thr ABCB1 p.Arg492Cys ABCB1 p.Met986Val Representative genetic polymorphisms in MDR1 Position Location EŠect A1aW-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G exon 2 Asn21Asp G5W-25T intron G5W-35C intron T307C exon 5 Phe103Leu C6W＋139T intron C6W＋145T intron A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T exon 12 silent C12W＋44T intron C1474T exon 13 Arg492Cys T17W-76A intron A17W＋137G intron C2650T exon 21 silent G2677A,T exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent See references 27, 32-36. Login to comment 104 ABCB1 p.Thr1236Cys The ˆrst preliminary report on the eŠects of their genotypes was presented by von Ahsen et al., who indicated that the maintenance dose or dose-adjusted Cmin,ss of CsA was independent either of MDR1 C3435T or CYP3A4 genotype, after an analysis of 124 Caucasian renal transplant recipients.146) Mai et al. indicated no eŠects of MDR1 G2677T or C3435T on the dose-adjusted AUC0-12,ss, Cmin,ss and C2,ss of CsA in 95 renal transplant recipients, and an analysis based on the G2677TW C3435T haplotype56) also failed to predict the pharmacokinetics of CsA.147) Kuzuya et al. also reported no eŠects of MDR1 T-129C, T1236C, G2677A,T and C3435T on the dose-adjusted AUC0-2,ss of CsA in 57 renal transplant recipients.148) In 2002, the Consensus on Neoral C2: Expert Review in Transplantation (CONCERT) conference was convened to undertake a multidisciplinary review of pharmacokinetic and clinical data on CsA microemulsions, and an international consensus on a patient management strategy with the oral administration of a CsA microemulsion has come to be presented based on the monitoring of C2,ss as a surrogate marker of AUC0-4,ss, AUCss up to 4 hr after oral administration, which was recently found to be predictive of immunosuppressive eŠects and toxicity, when compared with conventional C0,ss monitoring.175-178) One important issue to be resolved is the existence of ``slow absorbers'', who show a Cmax,ss at 4 hr or later, and are susceptible to over-dosing of CsA based on C2,ss monitoring. Login to comment