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Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients.
J Clin Pharm Ther. 2007 Oct; 32(5):505-15.JC

Abstract

BACKGROUND AND OBJECTIVE

Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter-individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL-10 genetic polymorphisms in the variability of population pharmacokinetic parameters.

METHODS

Tacrolimus blood concentration data (n = 1106) were collected from 104 full liver transplant patients and were analysed using a non-linear mixed-effects modelling program (nonmem). The CYP3A5*3, MDR1 G2677T/A and C3435T genetic polymorphisms were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The IL-10 G-1082A variant was studied by allele-specific PCR method.

RESULTS AND DISCUSSION

The liver function in patients as indicated by the total bilirubin level (TBIL) and different CYP3A5*3 genotypes in donors (CYPD) and recipients (CYPR) were observed to influence tacrolimus pharmacokinetic parameter of apparent clearance (Cl/F). The final regression model can be expressed as Cl/F = 15.9 - 1.88 TBIL + 7.65 CYPD + 7.00 CYPR. The relative standard errors (%RSE) of the parameter estimation were lower than 30% and the residual variability of tacrolimus trough blood concentration was 2.81 ng/mL. No significant effect of MDR1 and IL-10 polymorphisms was observed on population pharmacokinetic parameter of tacrolimus within 175 days after liver transplantation.

CONCLUSION

The TBIL in patients and CYP3A5*3 genetic polymorphism in both donors and recipients contribute to the inter-individual variability of oral tacrolimus apparent clearance in Chinese adult liver transplant patients.

Authors+Show Affiliations

Department of Pharmacology, Basic Medical School, Health Science Centre, Beijing (Peking) University, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17875118

Citation

Li, D, et al. "Population Pharmacokinetics of Tacrolimus and CYP3A5, MDR1 and IL-10 Polymorphisms in Adult Liver Transplant Patients." Journal of Clinical Pharmacy and Therapeutics, vol. 32, no. 5, 2007, pp. 505-15.
Li D, Lu W, Zhu JY, et al. Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients. J Clin Pharm Ther. 2007;32(5):505-15.
Li, D., Lu, W., Zhu, J. Y., Gao, J., Lou, Y. Q., & Zhang, G. L. (2007). Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients. Journal of Clinical Pharmacy and Therapeutics, 32(5), 505-15.
Li D, et al. Population Pharmacokinetics of Tacrolimus and CYP3A5, MDR1 and IL-10 Polymorphisms in Adult Liver Transplant Patients. J Clin Pharm Ther. 2007;32(5):505-15. PubMed PMID: 17875118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients. AU - Li,D, AU - Lu,W, AU - Zhu,J-Y, AU - Gao,J, AU - Lou,Y-Q, AU - Zhang,G-L, PY - 2007/9/19/pubmed PY - 2007/12/8/medline PY - 2007/9/19/entrez SP - 505 EP - 15 JF - Journal of clinical pharmacy and therapeutics JO - J Clin Pharm Ther VL - 32 IS - 5 N2 - BACKGROUND AND OBJECTIVE: Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter-individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL-10 genetic polymorphisms in the variability of population pharmacokinetic parameters. METHODS: Tacrolimus blood concentration data (n = 1106) were collected from 104 full liver transplant patients and were analysed using a non-linear mixed-effects modelling program (nonmem). The CYP3A5*3, MDR1 G2677T/A and C3435T genetic polymorphisms were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The IL-10 G-1082A variant was studied by allele-specific PCR method. RESULTS AND DISCUSSION: The liver function in patients as indicated by the total bilirubin level (TBIL) and different CYP3A5*3 genotypes in donors (CYPD) and recipients (CYPR) were observed to influence tacrolimus pharmacokinetic parameter of apparent clearance (Cl/F). The final regression model can be expressed as Cl/F = 15.9 - 1.88 TBIL + 7.65 CYPD + 7.00 CYPR. The relative standard errors (%RSE) of the parameter estimation were lower than 30% and the residual variability of tacrolimus trough blood concentration was 2.81 ng/mL. No significant effect of MDR1 and IL-10 polymorphisms was observed on population pharmacokinetic parameter of tacrolimus within 175 days after liver transplantation. CONCLUSION: The TBIL in patients and CYP3A5*3 genetic polymorphism in both donors and recipients contribute to the inter-individual variability of oral tacrolimus apparent clearance in Chinese adult liver transplant patients. SN - 0269-4727 UR - https://www.unboundmedicine.com/medline/citation/17875118/Population_pharmacokinetics_of_tacrolimus_and_CYP3A5_MDR1_and_IL_10_polymorphisms_in_adult_liver_transplant_patients_ L2 - https://doi.org/10.1111/j.1365-2710.2007.00850.x DB - PRIME DP - Unbound Medicine ER -