Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction and pharmacogenetics

• Published in: Pediatric nephrology (Berlin, West) West), 2010-05, Vol.25 (5), p.965-969
• Main Authors: Leroy, Sandrine, Isapof, Arnaud, Fargue, Sonia, Fakhoury, May, Bensman, Albert, Deschênes, Georges, Jacqz-Aigrain, Evelyne, Ulinski, Tim
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - enzymology; Acute Kidney Injury - genetics; Adolescent; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Brief Report; Calcium Channel Blockers - adverse effects; Calcium channels; Competition; Complications and side effects; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Diarrhea; Diarrhea - complications; Drug interaction; Drug Interactions; Drug Monitoring; Drug therapy; Enterocytes; Enzymes; Gene polymorphism; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Kidney Transplantation; Kidneys; Male; Medicine; Medicine & Public Health; Nephrology; Organ transplant recipients; P-Glycoprotein; Pediatrics; Pharmacogenetics; Pharmacokinetics; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Risk groups; Tacrolimus; Tacrolimus - adverse effects; Tacrolimus - pharmacokinetics; Transplantation; Transplants & implants; Urology
• ISSN: 0931-041X; 1432-198X
• DOI: 10.1007/s00467-009-1402-8

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.