An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients

Satohiro Masuda, Ken ichi Inui

研究成果: Contribution to journalReview article査読

158 被引用数 (Scopus)

抄録

Calcineurin inhibitors, tacrolimus (FK506) and cyclosporine (ciclosporin A), are the primary immunosuppressive agents used on recipients of organ transplantations. The hepatic metabolism of these drugs by cytochrome P450 IIIA (CYP3A) subfamilies is considered a major eliminating process. The intestinal efflux-pump P-glycoprotein (Pgp) (multidrug resistance 1 [MDR1], ATP-binding cassette B1 [ABCB1]) and CYP3A4 have been demonstrated as important for the bioavailability of drugs, so called "absorptive barriers". Recently, an important role for CYP3A5 in the intestine for the oral clearance of drugs has been identified. Both tacrolimus and cyclosporine are substrates of Pgp, CYP3A4 and CYP3A5, and therefore, these molecules are potential pharmacokinetic factors with which to establish personalized dosage regimens for these drugs. Although the effect of single nucleotide polymorphisms in the MDR1/ABCB1 and CYP3A5 genes on the pharmacokinetics of immunosuppressant has been widely examined, some contradictions have been emerged. In living-donor liver transplant (LDLT) patients, the intestinal mRNA expression level of MDR1 and CYP3A5 genotyping both in the native intestine and in the grafted liver are suggested to be potential pharmacokinetic factors for adjusting initial dosage and predicting post-operative variation in the pharmacokinetics of tacrolimus. We review the pharmacokinetic and pharmacodynamic characteristics of these drugs including the large pharmacokinetic variation and potential individualized dosage adjustments based on the genomic information of transporters and metabolic enzymes as well as classical pharmacokinetic analyses based on therapeutic drug monitoring (TDM).

本文言語英語
ページ(範囲)184-198
ページ数15
ジャーナルPharmacology and Therapeutics
112
1
DOI
出版ステータス出版済み - 10 2006

All Science Journal Classification (ASJC) codes

  • 薬理学
  • 薬理学(医学)

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