The pharmacokinetics and metabolic disposition of tacrolimus: A comparison across ethnic groups

Mancinelli, Laviero; Frassetto, Lynda; Floren, Leslie Carstensen; Dressler, Dawna; Carrier, Steve; Bekersky, Ihor; Benet, Leslie Z.; Christians, Uwe

doi:10.1067/mcp.2001.113183

Cited by 190 publications

(132 citation statements)

References 28 publications

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“…Significant differences in the tacrolimus pharmacokinetic profile have been found in various ethnic groups. The mean tacrolimus dose is 96% higher in African American transplant recipients than in Caucasians or Asians (25,26). Maintenance of adequate levels of tacrolimus and cyclosporine is a critical issue in these patients (27,28).…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Zheng

Webber

Zeevi

et al. 2003

American Journal of Transplantation

247

174

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Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.

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Section: Discussionmentioning

confidence: 99%

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Zheng

Webber

Zeevi

et al. 2003

American Journal of Transplantation

247

174

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“…Some studies have demonstrated the contribution of the recipient CYP3A5 genotype on tacrolimus metabolism. Mancinelli et al (2001) found that tacrolimus pharmacokinetics were affected by differences of the intestine CYP3A5 genotype. A significant difference was also found in tacrolimus daily dose and tacrolimus C/D ratios between recipients carrying the CYP3A5 6986GG allele and recipients carrying the CYP3A5 6986AG/AA allele both at 2 and 3 weeks and 1 month after transplantation (Uesugi et al, 2006).…”

Section: Influence Of Age Time Course and Graft Liver Weight On Thementioning

confidence: 99%

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients

Wang¹,

Liu²,

Tong³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We examined the influence of the cytochrome P450 3A5 (CYP3A5) genes in both donors and recipients on the concentrationdosage ratio (C/D) of tacrolimus in Chinese liver transplant patients. Fifty-one adult liver transplant patients who received tacrolimus were included in this study. The CYP3A5 polymorphism in donors and recipients was determined at the time of transplantation, and tacrolimusbased immunosuppressive therapy was started based on each patient's genetic constitution. The relationship between the C/D of tacrolimus for 3 months after surgery and the CYP3A5 genotype was analyzed. A stepwise regression model was used to analyze the relationship between C/D of tacrolimus and genotype, time course, age, and liver weight in liver transplant patients. Three months after liver transplantation, C/D was both affected by the CYP3A5 genotype of both the donors and (2015) the recipients. The C/D of tacrolimus in patients with the CYP3A5*1 allele or carrying CYP3A5*1 allele in the liver was lower than that in CYP3A5*3/*3 patients with the CYP3A5*3/*3 genotype in the liver (P < 0.01). The CYP3A5*1 genotype in donors as well as in patients both contributes to interindividual variation in the C/D of tacrolimus in adult liver transplantation.

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“…Recent developments have improved understanding of the molecular mechanisms responsible for such interethnic differences. Genetic variations that may provide a molecular basis for ethnic differences in drug metabolizing enzymes (CYP 2C9 (4), 2C19 (5), 2D6 (6), and 3A4 (7)), drug transporter (Pglycoprotein (8), alpha-1 acid glycoprotein (9)), and drug receptors (adrenoceptors (10)). Their relevance for the clinical evaluation of drugs is attracting growing attention, especially, since the discussion on the acceptability of foreign clinical data has been set by the International Conference on Harmonization (11,12).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Oral Rosiglitazone in Taiwanese and Post Hoc Comparisons with Caucasian, Japanese, Korean, and Mainland Chinese Subjects

Chu

Pao

et al. 2007

J Pharm Pharm Sci

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-Purpose. Rosiglitazone, an insulin-sensitizing thiazolidinedione, acts as a ligand for the γ-subtype of the peroxisome proliferator-activated receptor in the regulation of glucose homeostasis and lipid metabolism. The aims of this study were to determine the pharmacokinetics of oral rosiglitazone in Taiwanese and to post hoc compare the ethnic differences among Caucasian, Japanese, Korean, and Mainland Chinese. Methods. Twelve Taiwanese healthy male subjects received 4 and 8 mg of rosiglitazone. Similar protocols were used in the previously unpublished studies conducted in 25 Caucasian, 32 Japanese, 8 Korean, and 12 Mainland Chinese healthy male subjects. The 4 mg dose data were used for ethnicity comparisons.Results. The respective pharmacokinetic properties of Taiwanese, Caucasian, Japanese, Korean and Mainland Chinese are: terminal half-life (hr): 4.18 ± 0.43, 3.96 ± 1.31, 3.83 ± 0.78, 4.70 ± 1.19 and 4.37 ± 0.63; C max (ng/ml): 384.1 ± 59.3, 260.2 ± 75.7, 401.9 ± 102.3, 345.3 ± 60.6, and 406.2 ± 52.0; AUC 0-inf (h·ng/ml): 2078 ± 433, 1249 ± 566, 1901 ± 397, 1938 ± 534, and 2158 ± 498. The C max and AUC 0-inf of Caucasian were significantly (p = 0.002, 0.008) lower and CL/F and V/F were significantly (p = 0.000, 0.003) higher than those of other races. These differences of C max , AUC 0-inf , CL/F and V/F between Caucasian and other races became insignificant after normalized by dose and weight. Conclusions. In a given dose by body weight, ethnicity had no significant impact on the pharmacokinetics of rosiglitazone in normal healthy volunteers.

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The pharmacokinetics and metabolic disposition of tacrolimus: A comparison across ethnic groups

Abstract: Significant differences in tacrolimus pharmacokinetics exist among the three different ethnic groups. Our results indicate that this may result from differences in intestinal CYP3A or P-glycoprotein activities.

Cited by 190 publications

References 28 publications

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients

Pharmacokinetics of Oral Rosiglitazone in Taiwanese and Post Hoc Comparisons with Caucasian, Japanese, Korean, and Mainland Chinese Subjects

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