Altered First-Pass Effects in a Liver Transplant Recipient Explained Intraindividual Variation in Calcineurin Inhibitor Concentrations: A Case Report

S. R. Malireddy, A. G. Pinto, N. P. Chalasani, J. C. Gorski, S. D. Hall

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background: The significant interindividual and intraindividual variability in the blood concentrations of the most commonly used calcineurin inhibitors such as tacrolimus and cyclosporine makes the exact dosing of these agents in transplant recipients very challenging. As both of these drugs have narrow therapeutic index and are metabolized by hepatic and intestinal cytochrome P450 3A, we tested the hypothesis that these variations are secondary to varying first-pass effects in the gut and the liver over a period of time. Case report: A liver transplant recipient, who had previously presented with tacrolimus toxicity on his usual dosing regimen and intolerant to standard doses of cyclosporine, was selected to undergo the study. Oral and intravenous midazolam was used as the probe to measure hepatic and intestinal CYP3A4 activities at two different time points (phases one and two). Small intestinal biopsies were also obtained for measuring CYP3A4 activity for in vitro studies. On serially determining the patient's hepatic and intestinal CYP3A activities, we concluded that the variability in the dosing requirements is due to altered first-pass effects in the intestine. Discussion: Transplant recipients receive multiple medications that may inhibit or induce these metabolizing enzymes, which eventually determine the concentrations of these narrow therapeutic agents. If no obvious etiology of intolerance to calcineurin inhibitors in a transplant recipient is identified, one should consider altered first-pass effects in the gut and the liver contributing to intraindividual variations in the blood concentrations.

Original languageEnglish (US)
Pages (from-to)1789-1791
Number of pages3
JournalTransplantation proceedings
Volume40
Issue number5
DOIs
StatePublished - Jun 1 2008

ASJC Scopus subject areas

  • Surgery
  • Transplantation

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