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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 6  |  Page : 1125-1136
The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients

1 Department of Clinical Pharmacy, Pharmacy College, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
2 Clinical Pharmacy Services, King Saud Medical City, Riyadh, Saudi Arabia
3 Department of Pediatric Nephrology, Queen Rania Abdulla Children Hospital, Royal Medica Services, Amman, Jordan

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Date of Web Publication13-Nov-2013


Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5*3 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5*1 and *3 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.

How to cite this article:
Shilbayeh S, Zmeili R, Almardini RI. The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients. Saudi J Kidney Dis Transpl 2013;24:1125-36

How to cite this URL:
Shilbayeh S, Zmeili R, Almardini RI. The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Mar 4];24:1125-36. Available from: https://www.sjkdt.org/text.asp?2013/24/6/1125/121268

   Introduction Top

Tacrolimus (TAC), as a potent immunosuppressive agent, in combination with mycophenolate mofetil or azothioprine and corticosteroids is frequently employed in most of the immunosuppressive protocols post-transplantation. TAC is a macrolide that has a narrow therapeutic scope in terms of efficacy and safety. Previous international studies demonstrated significant heterogeneity in the dose required to attain target blood concentrations, which was attributed to both genetic and ethnic factors. [1] However, initial dosing (priori) is still based on general guidelines. [2] Thereafter, subsequent (posteriori) individualization of the dosage regimen based on frequent therapeutic drug monitoring (TDM) is suggested to be crucial for avoiding under- and over-immunosuppression. However, a number of essential limitations are often associated with traditional TDM, but primarily because it can only be initiated when an immunosuppressant is administered; therefore, it is not informative for predicting the initial dosage. [3] Additionally, the subsequent monitoring to adjust the dose during the long-term follow-up requires extensive blood testing for drug concentrations and expends a substantial amount of the clinician's time and resources. Therefore, several conventional pharmacokinetic (PK) [4],[5] and population modeling studies based on the blood concentration of TAC have been conducted for about 20 years in an attempt to optimize TDM. [6] However, many of these population PK models were shown to have only limited predictive value with regard to explaining the variability in TAC exposure/drug concentrations. [7] Therefore, an alternative dose-individualization approach based on genetic information was suggested for post-transplant management using immunosuppressants, especially in the initial scenery of dose. [8],[9]

TAC is known to be a substrate of cytochrome P450 (CYP) 3A enzymes, in particular CYP3A4 and CYP3A5, which are encoded by the CYP3A4 and CYP3A5 genes, respectively. [1] However, CYP3A5 may play a more dominant role than CYP3A4 in the metabolism of TAC. [8] In addition, TAC is transported out of the intestine, liver and kidney cells via p-glycoprotein (P-gp), which is encoded by the multidrug resistance 1 (MDR1) gene. [10],[11] CYP3A5 is also found in these similar cells of CYP3A5 expressers. The difference in expression level and the bioactivity of these proteins due to several single nucleotide polymorphisms (SNPs) have been identified in their encoding genes and, therefore, were thought to partially explain the inter-individual variations of TAC PKs. [11],[12] In particular, the presence of an SNP in intron 3 CYP3A5 A6986G has been reported to result in the absence of functional CYP3A5 protein in homozygous carriers (CYP3A5 *3/*3). [13],[14] Moreover, a total of 50 SNPs have been identified in MDR1, including C1236T, G2677T/A and C3435T SNPs in exons 12, 21 and 26, respectively, which were assumed to form different haplotypes in different ethnic groups. [15] Some of the genetic polymorphisms of MDR1 were found to influence the expression level and function of P-gp, yet conflicting effects were revealed. At first, the MDR1 cDNA C3435T SNP was found to reduce the expression level of P-gp in the intestinal mucosa, placenta and kidney. [16],[17],[18],[19] However, it was reported that the MDR1 mRNA level was actually higher in the intestinal mucosa carrying a T allele compared with the C allele. [20]

During the last decade, pharmacogenetic studies involving kidney, heart and liver transplant recipients were conducted to examine the individual effects of known CYP3A4/5 and MDR1 SNPs on the TAC PK parameters [daily dose requirement (D), trough concentration (C 0 ), C 0 /D, D/C 0 and the area under the concentration-time curve (AUC)] and/or pharmacodynamic outcomes in these patients [acute rejection, long-term patient and graft survival, infection, nephrotoxicity, diabetogenesis and hypertension]. [8],[9] Yet, the influence of these SNPs remains unclear, with complex and inconsistent conclusions.

Because of the low frequencies in genetic polymorphisms, it was difficult to explain the large PK variation only by the CYP3A4 genotypes and so far the effect of CYP3A4-A392G SNP is considered limited and may be confounded by ethnicity or genetic linkage with CYP3A5 and MDR1 SNPs. [15],[21],[22] However, the majority of previous reports on recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5*3 SNP on the PK of TAC, [8] and a lesser influence on outcomes. [9] However, the impact of CYP3A5 polymorphism on TAC PK was found to be modified by time interval post-transplant. [23],[24],[25] Similarly, the impact of MDR1 SNPs on either TAC PKs or pharmacodynamics remains controversial across different studies in various ethnic groups. [8],[9],[12],[22],[26],[27],[28],[29],[30] While few investigations in some ethnic minorities displayed a significant or slight significant association with either pk [12],[22],[26],[27] or pharmacodynamic measures, [28],[29], [30] several others have failed to show such associations. [8],[9]

Additionally, most of these studies were conducted to fully understand the molecular mechanisms related to the inter-individual variations of TAC PK in adults. Yet, similar data of TAC in pediatric populations in whom the intra- and inter-subject variations are likely to be even greater is currently limited. In fact, it is essential to consider the potential for age-related changes in CYP3A4/5 enzyme levels due to both environmental and biological maturation (physiological development) factors, particularly because younger children will be receiving immunosuppressive therapy throughout their lives. [31]

The frequency of the CYP3A5*3 allele is highly dependent on ethnicity, with being mostly detected in Caucasian subjects, 60-90% of whom do not express CYP3A5 protein. Conversely, much more than 50% of African subjects have at least one CYP3A5*1 allele and express CYP3A5 protein. [15] Andrews et al [32] stated that African-European recipients of renal transplant needed twice the dose of TAC as Caucasian recipients to achieve the target blood concentration.

To be best of our knowledge, no pharmacogenetic studies, documented with international publications, have been performed on the Jordanian population to uncover the frequency as well as the types of polymorphisms found in CYP3A5 or MDR1 genes. The objectives of our study were therefore (1) to describe the prevalence of polymorphisms of CYP3A5 and MDR1 among the Jordanian pediatric renal transplant population, (2) to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the early and maintenance phases post-transplant and (3) to examine the impact of these genotypes on the short- or long-term clinical outcomes during the prospective follow-up of the same population. The latter objective will be discussed in another article.

   Methodology Top

Patients and data collection

Thirty-eight Jordanian pediatric renal transplant recipients who received kidney grafts between January 2007 and January 2009 were included in this study. The study protocol was approved by the Ethics Committee of Royal Medical Services. Informed consent was obtained from each patient and/or their parents. Details of the TAC-based immunosuppressive regimen and its routine therapeutic drug monitoring have been described elsewhere. [33] The whole blood C 0 was measured 12 h post-dose at various time points using a microparticle enzyme immunoassay (Abbott IMx, Abbott Laboratories, Abbott Park, Illinois, USA). The target concentrations were 10-20 ng/mL during the first month after transplantation and 5-10 ng/mL thereafter.


Genotyping of CYP3A5*3 and *1

Genomic DNA was extracted from 400 μL of whole blood using a phenol-chloroform kit (PIERCE, Rockford, IL, USA). The polymerase chain reaction (PCR) reaction was carried out in 20 μL of a solution containing 2 μL of 10x PCR Gold Buffer, 2 mM MgCL 2 , 80 μM each of dNTPs, 50 pmol each of primers, 50 ng of genomic DNA and 0.6 U of AmpliTaq Gold (Applied Biosystem, Grand Island, NY, USA). The forward primer was 5'-ATGGAGAGT-GGCATAGGA-GATA-3', but a modified reverse primer (5'-TGTGGTCCAAACAGGG-AAGAGAT-3') was used on the basis of the reported sequence (GenBank accession number: AF355800). The PCR conditions were 8 min at 94°C, followed by 40 cycles of 30 s at 94°C, 30 s at 59°C and 30 s at 72°C, and a final extension for 10 min at 72°C. The PCR product was detected on a 2% agarose gel by means of ethidium bromide staining.

Genotyping of MDR1 at exon 26

Genotyping of MDR1 at exon 26 C3435T SNP was performed by using forward: 5'-TGCTGGTCCTGAAGTTGATCTGTGAAC-3' and reverse 5'-ACATTAIGGCAGTGAC-TCGATGAAGGCA-3' primers and through the employment of Mbol endonuclease.

   Statistical Analysis Top

All results were expressed as the mean ± SD. TAC dose-adjusted trough levels (C 0 /D) during the early (7 and 14 days) and maintenance phases (1, 3, 6, 9 and 12 months post-transplant) were calculated as the trough level (ng/mL) divided by the dose (mg/kg/day). The distribution of continuous and categorical data across various genotypes was evaluated using parametric and non-parametric tests where suitable. Mean values of serum creatinine, creatinine clearance, D, C 0 and C 0 /D associated with various genotypes were compared by Student's t-test, Wilcoxon test and ANOVA test (with post hoc Tukey's test) using the GraphPad Prism version 5.02 for windows (GraphPad Software, San Diego, CA, USA).

   Results Top

The CYP 3A5 *1/*1, *1/*3 and *3/*3 genotypes were detected in two (5.3%), four (10.5%) and 32 (84.2%) of the 38 pediatric patients, respectively, while the MDR1 C3435T CC, 3435CT and 3435TT were detected in 15 (39.5%), 15 (39.5%) and eight (21.1%) pediatric patients, respectively. Both genotype distributions did not deviate from the Hardy- Weinberg equilibrium. The distribution of baseline patient characteristics [Table 1] did not differ significantly within the subcategories of the two genotypes. Additionally, serum albumin, hematocrit, hemoglobin, total billirubin and liver enzymes did not change significantly and were comparable among the different genotypes (data not shown) throughout the observation period (22 ± 15 months).
Table 1: The distribution of baseline demographic and clinical characteristics of the pediatric patients stratified by CYP3A5 and MDR1 genotypes.

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Surprisingly, there were no significant differrences in D, C 0 or C 0 /D among each genotype group of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation [Table 2]. Moreover, after combining the C 0 /D levels of CYP3A5 expressers (CYP3A5 *1/*1 + *1/*3), the difference remained non-statistically significant in comparison with the CYP3A5 non-expressers (CYP3A5 *3/*3) at any time point [Figure 1], whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably higher TAC levels were observed in the TT genotype as compared with the combined group of TC and CC genotypes near the beginning of the maintenance phase post-transplantation [Figure 2]. However, the difference became non-significant beyond 3 months.
Table 2: The impact of CYP3A5 and MDR1 genotypes on tacrolimus pharmacokinetics.

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Figure 1

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Figure 2

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To examine the combined effect of CYP3A5 and MDR1 polymorphisms, the patients were divided into three genotype groups: *3/*3 + MDR1 CC (n = 11), *3/*3 + MDR1 CT (n = 13) and *3/*3 + MDR1 TT (n = 8). Interestingly, pediatrics who had the combined mutations in CYP3A5 and MDR1 (*3/*3 + MDR1 TT) displayed significantly higher C 0 /D levels [Figure 3], suggesting a possible additive effect due to interaction between the first two SNPs, whereas a comparison between the other available genotype combinations - *1/*1 + MDR1 CC (n=2), *1/*3 + MDR1 CT (n=2) and *1/*3 + MDR1 CC (n = 2) - did not demonstrate any statistical significance.
Figure 3

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   Discussion Top

Ethnic variation in TAC PKs has been well established. [12],[34],[35] Therefore, a significant heterogeneity in the dosage required to achieve target blood concentrations was noted. [12],[32] This was partially attributed to genetic factors. [1],[8] To the best of our knowledge, there are no data demonstrating whether the Jordanian pediatric population has different PKs compared with Caucasians, African Americans or Asians. This is the first pharmacogenetic prospective followup study to be conducted involving Jordanian pediatric renal transplant recipients to evaluate the impact of CYP3A5 and MDR1 polymorphisms on TAC PKs and pharmacodynamics.

With regard to CYP3A5, our patients exhibited genotype frequencies more similar with those already described in Caucasians and Japanese populations; however, these genotype frequencies were different from the African-American populations. [14],[15],[36],[37] The frequency of wild-type CYP3A5 *1/*1 genotype was more comparable to Asians (7-12.2%), higher than Caucasians (0%), but less than African-Americans (25%). The frequency of heterozygote CYP3A5 *1/*3 genotype was lower than all populations (25-57.1%). However, the frequency of the homozygous *3/*3 genotype was more comparable to Caucasians (70.4- 83.1%) but significantly higher than Asians (31.1-60.5%) and African-Americans (35%). For the MDR1 exon 26 polymorphism, the distribution of wild-type CC, heterozygote CT and homozygous TT was very similar to that reported for Caucasians (35.8, 42% and 22.2%, respectively), [38] while it was different from Chinese (25, 43.8 and 31.3%, respectively) and Indians (18.4, 36.8 and 44.8%, respectively). [15] Some studies in adults have reported a decrease in the TAC dosage requirements to achieve similar trough concentrations with increasing time post-transplant. [23],[24],[25],[39],[40] Declines in corticosteroid dosage and recovered hematocrit and albumin levels with time have been postulated as reasons for a decrease in TAC clearance, [40] whereas in other studies the opposite effect of corticosteroid dosage on TAC clearance was demonstrated. [41] However, the influence of time post-transplant on TAC PKs in pediatrics is not clear. While a previous study demonstrated significantly higher dosage requirements in the first month compared with that required to achieve the same TAC target 3.5 years later, others observed either decreased [42] or no changes [43] with elapsed time after transplantation.

In the present study, the body weight-adjusted dose of TAC differed significantly between the early (<3 months) and maintenance stages (0.193 ± 0.07 vs 0.1597 ± 0.06; P-value Wilcoxon test = 0.0002); however, the C 0 /D level was non-statistically significant during the long-term follow-up duration (P = 0.775), probably due to continuous dose modifications according to TDM. Several other possible explanations may have contributed to our current observation. First, the dose of corticosteroid, which is known to increase CYP3A5 activity resulting in reduction of TAC C 0 , was significantly reduced during the first 3 months. In the current study, the mean initial dose of prednisolone and the dose in the 3 rd month were 40.8 ± 15.7 and 9.7 ± 3.9 mg/day, respectively, while that in the 12 th month was 5.18 ± 0.97 mg/day (P <0.0001). This has resulted in higher trough levels despite the significant progressive reduction in TAC dose from 0.193 during the 3 rd month to 0.1597 mg/kg/day 1 year post-transplant (P = 0.0002).

Secondly, hematocrit [44] and albumin [45] concentrations, which were found to have a significant impact on TAC clearance and level, did not increase significantly beyond the first 2 weeks post-transplant in our pediatrics and remained relatively constant during the studied period. In accordance with the findings in previous studies, the majority (>70%) of our pediatric patients had hematocrit values consistently higher than 33%, below which it was only found to significantly increase the TAC clearance. [46],[47] This may have contributed to less variability in our TAC levels with increase in time elapsed since transplantation.

Regardless of ethnicity, the majority of studies in the recipient of organ transplantation has demonstrated that the CYP3A5 *1 allele carriers (CYP3A5 expressers) needed a larger TAC dose and sometimes longer time to reach the target C 0 level compared with the CYP3A5 *3/*3 carriers (CYP3A5 non-expressers), despite TDM. [12],[23],[26],[38],[48] Yet, in other reports, no significant association was found between CYP3A5 genotypes and TAC unadjusted [49],[50],[51] or dose-adjusted [52] C 0 concentrations. In our pediatric study, no associations were found between dosage requirements or C 0 /D levels and CYP3A5 polymorphism, and these findings were not subjected to time-dependent change. The masking of the effects of CYP3A5 genotypes on TAC PKs in our pediatrics may be attributed to the level of expression of intestinal or hepatic CYP3A5 rather than their metabolic capabilities, which may be modified by environmental conditions and are likely to undergo developmental changes (e.g., bowel length, gastric pH, hepatic blood flow) as a function of age. [31],[53] Moreover, CYP3A5 is expressed in almost 50% of all infants' livers, but may possibly be found in only 29% of adult livers. [54] This could partially explain our contradictory findings to those obtained in adult renal transplant studies. [12],[23],[38],[49],[55] Additionally, a fat-rich diet in Jordan, the small number of patients carrying the wild (*1) allele in our study, the difference of transplant etiologies, concurrent illnesses, higher corticosteroid and lower co-medication (MMF, MF, AZA) compared with other adult [12],[23],[26],[38],[56] or pediatric [56] immunosuppressive regimens could contribute to unrevealing of the impact of CYP3A5 polymorphisms on TAC level in our pediatric population. This controversy emphasized the need for further larger and more controlled prospective studies in pediatric transplant patients to confirm the independent impact of CYP3A5 on TAC PKs and long-term clinical outcomes. Another important fact that should be taken into account in designing new studies is the employment of more accurate exposure indices than C 0 , such as the area under the TAC blood concentration-time curve during one dosing interval at steady state (AUC ss ). [34]

The impact of MDR1 polymorphisms on TAC PKs remains uncertain, with most studies performed in adults, [12],[22],[23],[26],[27],[52],[55],[57],[58] whereas limited data are available for the pediatric population. [47],[56] In our study, the MDR1 3435TT variant genotype displayed higher TAC C 0 /D levels as compared with the heterozygote (CT) and wild type (TT) in the first part of the maintenance phase post-transplant. Such findings confirmed previous suggestions of possible lower functional activity of P-gp due to the lesser expression associated with the T allele [18],[19],[20],[21] rather than the C allele. Yet, the difference turned into statistically non-significant beyond the 3 rd month. Conversely, one study in pediatric heart transplant patients has found a significant association of MDR1 C3435T with TAC C 0 /D at 6 and 12 months, but not at 3 months. [56] This could be attributed to the dissimilarity in physiologic factors underlying the two disease conditions, causing a variable increase in the MDR1 expression level. Additionally, our results were in contrast to several data from adult patients [23],[49],[52],[55],[59] as well as the inadequate information currently available from pediatrics, [47] which demonstrated no association of MDR1 polymorphisms with any PK parameters of TAC at any time period. However, our observation was in line with some recent studies in adult ethnic minorities, [12],[22],[26],[27],[57],[58],[60] reflecting the variable importance of MDR1 polymorphisms to different populations.

Although the majority of previous investigations have only appraised the influence of individual SNPs, haplotype analyses involving calcineurin inhibitors have proposed that multiple polymorphism combinations may interact to accentuate or conceal the independent effect of an SNP. [8] This may explain why individual SNP analysis may produce narrow and frequently contradictory impacts, particularly in small studies or those involving a population of low frequency of a variant allele. [52] Previous studies reported high frequencies of both the MDR1 3435T and the CYP3A5*3 variant alleles in the same populations, which advocated a possible linkage disequilibrium between these polymorphisms. [26],[61],[62] In agreement, all TT carriers in our population were CYP3A5 non-expressors (*3/*3). Interestingly, the obscured effect of the CYP3A5*3 allele was revealed after stratifying our pediatric group and comparing the PK parameters of TT and *3*3 simultaneous carriers to different combination polymorphisms. Similarly, the association between various MDR1 gene SNPs and CYP3A5 SNP were evaluated in several studies. Anglicheau et al [38] in a study of 81 renal transplant recipients declared a cumulative effect of MDR1 mutation at exon 26, 21 and 12 on TAC PKs compared with the wildtype haplotype. However, in contrast to our results, Loh et al [26] recently reported higher TAC C 0 /D levels in patients with a *3*3 and CC genotype combination compared with a *1*3 and CT genotype combination, suggesting that the difference is mostly due to the effect of CYTP3A5 SNP. Conversely, Wang et al [63] in a study of 81 lung transplant recipients demonstrated that MDR1 haplotypes were associated with TAC requirements, independent of the CYP3A5 genotype. In consistent with our finding, while all patients were known to be CYP3A5 *3/*3 expressers, patients with the 1236T-2677T-3435T + 1236T-2677T-3435T genotype had a significantly higher C 0 /D compared with the 1236C-2677G-3435C + 1236C-2677G-3435C genotype. Additionally, a recent population PK study revealed that the combination of MDR1 and CYP3A5*3 genetic polymorphisms has a relatively strong influence on the inter-individual variability of TAC clearance, with patients who are CYP3A5 expressers and simultaneously CC-GG-CC carriers having three-fold higher rates than those who are *3/*3 and TT-TT-TT carriers. [60]

In our study, we tested only the C3435T SNP of MDR1. Because this SNP was reported to be a silent polymorphism that did not result in any amino acid changes, the conflicting results of these studies and our own may be partly due to linkage disequilibrium with other functional polymorphisms within the MDR1 gene. Whether our observed results are mostly attributed to further linkage disequilibrium with the MDR1 SNPs in exons 12 and 21 remain to be examined. However, at the moment, we cannot exclude that dose adjustments based on both SNPs (CYP3A5 and MDR1 C3435T) should, ideally, be considered.

In conclusion, we found no significant time-dependent variability in TAC PKs after renal transplantation in our pediatric patients. Based on pharmacogenetic evaluation in this Jordanian study, the independent impact of CYP3A5 SNPs on TAC PKs was not evident in either the early or the maintenance phase, demonstrating the need for further large-scale studies to increase our knowledge about their effects on clinical outcome before application in routine practice. Indeed, in the light of the currently observed very high prevalence of *3 allele (89.5%) in the Jordanian population, we speculate to obtain more significant inter-genotype differences in a larger sample size study. However, for the effect of MDR1 C3435T polymorphism, the TT patients required a lesser dosage of TAC to achieve similar blood levels compared with CC/CT patients, remarkably near the beginning of the maintenance phase. Interestingly, an additive effect on TAC PKs was revealed in our pediatric renal transplant recipients who had both TT and *3/*3 SNPs, resulting in higher TAC C 0 /D levels compared with other *3/*3 patients who had other MDR1 C3435T genotypes. This suggested a possible linkage disequilibrium between the two polymorphisms and highlighted the need for considering dosage individualization based on both genotypes, particularly in pediatric patients. However, taken together, our data advocated that further molecular investigations are still required to explore the mutual relationship between CYP3A5 and MDR1 genotypes or haplotypes in affecting the immunosuppressant therapy in different ethnic and age categories.

   References Top

1.Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43:623-53.  Back to cited text no. 1
2.van Hooff JP, Boots JM, van Duijnhoven EM, Christiaans MH. Dosing and management guidelines for tacrolimus in renal transplant patients. Transplant Proc 1999;31(7A):54-7S.  Back to cited text no. 2
3.Wallemacq PE. Therapeutic monitoring of immunosuppressant drugs. Where are we? Clin Chem Lab Med 2004;42:1204-11.  Back to cited text no. 3
4.Jørgensen KA, Povlsen JV, Madsen S, et al. Two-hour blood tacrolimus levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal transplant patients. Transplant Proc 2002;34: 1721-2.  Back to cited text no. 4
5.Park SI, Felipe CR, Pinheiro-Machado PG, Garcia R, Tedesco-Silva H Jr, Medina-Pestana JO. Circadian and time-dependent variability in tacrolimus pharmacokinetics. Fundam Clin Pharmacol 2007;21:191-7.  Back to cited text no. 5
6.Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: Report of the European Consensus Conference. Ther Drug Monit 2009;31:139-52.  Back to cited text no. 6
7.Macchi-Andanson M, Charpiat B, Jelliffe RW, Ducerf C, Fourcade N, Baulieux J. Failure of traditional trough levels to predict tacrolimus concentrations. Ther Drug Monit 2001;23(2):129-33.  Back to cited text no. 7
8.Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet 2010;49:141-75.  Back to cited text no. 8
9.Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide poly­morphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors:Part II. Clin Pharmacokinet 2010;49:207-21.  Back to cited text no. 9
10.Hashimoto Y, Sasa H, Shimomura M, Inui K. Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm Res 1998;15:1609-13.  Back to cited text no. 10
11.Hebert MF. Contribution of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 1997;27:201-14.  Back to cited text no. 11
12.Macphee IA, Fredericks S, Tai T, et al. Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002;74:1486-9.  Back to cited text no. 12
13.Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 2001;11:773-9.  Back to cited text no. 13
14.Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383-91.  Back to cited text no. 14
15.Chowbay B, Zhou S, Lee EJ. An interethnic comparison of polymorphism of the genes encoding drug-metabolising enzymes and drug transporters: Experience in Singapore. Drug Metab Rev 2005;37:327-78.  Back to cited text no. 15
16.Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphism of the human multidrug resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473-8.  Back to cited text no. 16
17.Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European American and African Americans. Clin Pharmacol Ther 2001;70:189-9.  Back to cited text no. 17
18.Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: Relation to genetic polymorphism of multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 2001;297:1137-43.  Back to cited text no. 18
19.Siegsmund M, Brinkmann U, Scháffeler E, et al. Association of the P-glycoprotein transporter MDR1 (C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 2002;13:1847-54.  Back to cited text no. 19
20.Nakamura T, Sakaeda T, Horinouchi M, et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in doudenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002;71:297-303.  Back to cited text no. 20
21.He P, Court MH, Greenblatt DJ, Von Moltke LL. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 2005;77:373-87.  Back to cited text no. 21
22.Hesselink DA, van Schaik RH, van Agteren M, et al. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimustreated renal transplant recipients. Pharmacogenet Genomics 2008;18:339-48.  Back to cited text no. 22
23.Satoh S, Kagaya H, Saito M, et al. Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients. Br J Clin Pharmacol 2008;66: 207-14.  Back to cited text no. 23
24.Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clnical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther 2004;75:434-47.  Back to cited text no. 24
25.Kuypers DR, Claes K, Evenepoel P, et al. Time-related clinical determinants of long-term tacrolimus pharmacokinetics in combination the­rapy with mycophenolic acid and corticosteroids. Clin Pharmacokinet 2004;43: 741-62.  Back to cited text no. 25
26.Loh PT, Lou HX, Zhao Y, Chin YM, Vathsala A. Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients. Transplant Proc 2008;40:1690-5.  Back to cited text no. 26
27.Fredericks S, Moreton M, Reboux S, et al. Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements. Transplantation 2006;82: 705-8.  Back to cited text no. 27
28.Zheng HX, Zeevi A, McCurry K, et al. The impact of pharmacogenomics factors on acute persistent rejection in adult lung transplant patients. Transpl Immunol 2005;14:37-42.  Back to cited text no. 28
29.Yamauchi A, Ieiri I, Kataoka Y, et al. Neurotoxicity induced by tacrolimus after liver transplantation: Relation to genetics polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002;74:571-2.  Back to cited text no. 29
30.Herbert MF, Dowling AL, Gierwatowski C, et al. Association between ABCB1 (multidrug resistance transporter) genotype and post-liver transplantation renal dysfunction in patients receiving calcineurin inhibitors. Pharmacogenetics 2003;13:661-74.  Back to cited text no. 30
31.del Mar Fernandez De Gatta M, Santos-Buelga D, Dominguez-Gil A, García MJ. Immunosuppressive therapy for paediatric transplant patients: Pharmacokinetic considerations. Clin Pharmacokinet 2002;41:115-35.  Back to cited text no. 31
32.Andrews PA, Sen M, Chang RW. Racial variation in dosage requirements of tacrolimus. Lancet 1996;348:1446.  Back to cited text no. 32
33.Shilbayeh SA, Hazza I. Pediatric renal transplantation in the Jordanian population: The clinical outcome measures of long-term follow-up. Pediatr Neonatol 2012;53:24-33.  Back to cited text no. 33
34.Felipe CR, Silva Jr HT, Machado PG, Garcia R, da Silva Moreira SR, Pestana JO. The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. Clin Transplant 2002;16:262-72.  Back to cited text no. 34
35.Mancinelli LM, Frassetto L, Floren LC, et al. The pharmacokinetics and metabolic disposition of tacrolimus: A comparison across ethnic groups. Clin Pharmacol Ther 2001;69:24-31.  Back to cited text no. 35
36.Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characteri-zation of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383-91.  Back to cited text no. 36
37.Hiratsuka M, Takekuma Y, Endo N, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur J Clin Pharmacol 2002;58:417-21.  Back to cited text no. 37
38.Anglicheau D, Verstuyft C, Laurent-Puig P, et al. Association of the multidrug resistance-1 gene single -nucleotide polymorphism with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14:1889-96.  Back to cited text no. 38
39.Pou L, Brunet M, Andres I, Rodamilans M, Lopez R, Corbella J. Influence of posttransplant time on dose and concentration of tacrolimus in liver transplant patients. Transpl Int 1998;11 Suppl 1:S270-1.  Back to cited text no. 39
40.Undre NA, Schafer A. Factors affecting the pharmacokinetics of tacrolimus in the first year after renal transplantation European Tacrolimus Multicentre Renal Study Group. Transplant Proc 1998;30:1261-3.  Back to cited text no. 40
41.Satomura K, Ozaki N, Okajima H, et al. Pharmacokinetics of FK 506 in living-related liver transplantation. Transplant Proc 1996;28: 1005.  Back to cited text no. 41
42.Moreno M, Manzanares C, Castellano F, et al. Monitoring of tacrolimus as rescue therapy in pediatrics liver transplantation. Ther Drug Monit 1998;20(4):376-9.  Back to cited text no. 42
43.McDiarmid SV, Colonna JO 2nd, Shaked A, Vargas J, Ament ME, Busuttil RW. Differences in oral FK506 dose requirements between adult and pediatric liver transplant patients. Transplantation 1993;55:1328-32.  Back to cited text no. 43
44.Chow FS, Piekoszewski W, Jusko WJ. Effect of hematocrit and albumin concentration on hepatic clearance of tacrolimus (FK506) during rabbit liver perfusion. Drug Metab Dispos 1997;25:610-6.  Back to cited text no. 44
45.Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ. Changes in tacrolimus distribution in blood and plasma protein binding following liver transplantation. Ther Drug Monit 2004;26:506-15.  Back to cited text no. 45
46.Staatz CE, Willis C, Taylor PJ, Tett SE. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin Pharmacol Ther 2002;72:660-9.  Back to cited text no. 46
47.Zhao W, Elie V, Roussey G, et al. Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther 2009;86: 609-18.  Back to cited text no. 47
48.Ferraresso M, Tirelli A, Ghio P, et al. Influence of the Cyp3a5 genotype on tacrolimus pharmacokinetics and pharmaco-dynamics in young kidney transplant recipients. Pediatr Transplant 2007;11:296-300.  Back to cited text no. 48
49.Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:245-54.  Back to cited text no. 49
50.Thervet E, Anglicheau D, King B, et al. Impact of cytochrome P450 3A5 genetic polymerphism on tacrolimus doses and concentrationto-dose ratio in renal transplant recipients. Transplantation 2003;76:1233-5.  Back to cited text no. 50
51.Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol 2008;103:546-52.  Back to cited text no. 51
52.Mai I, Perloff ES, Bauer S, et al. MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients. Br J Clin Pharmacol 2004;58:548-53.  Back to cited text no. 52
53.Przepiorka D, Blamble D, Hilsenbeck S, Danielson M, Krance R, Chan KW. Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 2000;26:601-5.  Back to cited text no. 53
54.Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capacities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol 1990;38:207-13.  Back to cited text no. 54
55.Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmaco-genetics 2004;14:147-54.  Back to cited text no. 55
56.Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003;3:477-83.  Back to cited text no. 56
57.Akbas SH, Bilgen T, Keser I, et al. The effect of MDR1 (ABCB1) polymorphism on pharmacokinetics of tacrolimus in Turkish renal transplant recipients. Transplant Proc 2006;38: 1290-2.  Back to cited text no. 57
58.Cheung CY, Op den Buijsch RA, Wong KM, et al. Influence of different allelic variants of the CYP3A and ABCB1 genes on tacrolimus pharmacokinetic profile of Chinese renal transplant recipients. Pharmacogenomics 2006; 7: 563-74.  Back to cited text no. 58
59.MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004; 4:914-9.  Back to cited text no. 59
60.Musuamba FT, Mourad M, Haufroid V, Delattre IK, Verbeeck RK, Wallemacq P. Time of drug administration, CYP3A5 and ABCB1 genotypes, and analytical method influence tacrolimus pharmacokinetics: A population pharmacokinetic study. Ther Drug Monit 2009; 31:734-42.  Back to cited text no. 60
61.Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 2004;75: 422-33.  Back to cited text no. 61
62.Yates CR, Zhang W, Song P, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 2003;43:-555-64.  Back to cited text no. 62
63.Wang J, Zeevi A, McCurry K, et al. Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5 *3/*3 non-expressers. Transpl Immunol 2006;15:235-40.  Back to cited text no. 63

Correspondence Address:
Sireen Shilbayeh
Pharmacy College, Department of Clinical Pharmacy, Princess Nourah University, Riyadh
Saudi Arabia
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DOI: 10.4103/1319-2442.121268

PMID: 24231473

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