Significance of CYP Enzyme Phenoconversion in Transplant Immunosuppression and Chronic Kidney Disease.
Déri Máté Tamás
Pharmacology and Pharmacy
Dr. Szőke Éva
Experimentális és klinikai farmakológia
Dr. Szökő Éva
Dr. Monostory Katalin
Dr. Csala Miklós egyetemi tanár
Dr. Tihanyi Károly tudományos tanácsadó
Dr. Köles László habil. egyetemi docens
Dr. Kulcsár Péter István tudományos munkatárs
Dr. Tamási Viola egyetemi docens
Inter- and intra-individual variability in human drug metabolism is primarily attributed to genetic polymorphisms of drug-metabolizing enzymes; however, external (medication, alcohol consumption, smoking) and internal factors (gender, age, hormonal status, disease) can also contribute to the variability. CYPtest™ diagnostic system for the estimation of patients’ drug-metabolizing capacity is based on integrative analysis of relevant polymorphisms and mRNA expression of CYP genes. Because of the low levels of CYP mRNA expression in some clinical samples and the limited availability of biological samples, it was necessary to optimize the method. Following methodological optimization, we investigated mRNA expression of 4 important drug-metabolizing CYP enzymes (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) in patients with end-stage renal disease and in organ donors with healthy renal function. In patients with impaired renal function, CYP mRNA levels were significantly lower than in organ donors. In heart transplant patients, the relationship between early postoperative CYP3A status (CYP3A5 genotype and CYP3A4 mRNA expression) and tacrolimus exposure was also assessed. Recipients’ CYP3A status was associated with tacrolimus C0/D blood levels and dose requirement for therapeutic blood concentration. In cardiac transplant recipients, corticosteroid therapy with continuously reduced dosing in the 15-month period after surgery was found to affect CYP3A4 mRNA expression and consequently CYP3A4-mediated drug metabolism. Furthermore, in liver transplant patients, the role of the liver graft CYP3A5 genotype (the presence of CYP3A5*1 allele) in tacrolimus blood levels was confirmed in the early postoperative period, while a significant role of intestinal genotype (the presence of CYP3A5*1 allele) was not observed. Personalized therapy with appropriate dosing adjusted to the patients’ drug-metabolizing capacity can contribute to the reduction of adverse reactions and to the improvement of graft/patient survival.