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Sequential Analysis of Tacrolimus Dosing in Adult Lung Transplant Patients With ABCB1 Haplotypes

From the School of Pharmacy, University of Southern California, Los Angeles (Dr Zheng, Dr Burckart); School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Zeevi, Dr McCurry, Dr Webber, Dr Iacono); and Department of Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee (Dr Schuetz, Dr Zhang, Dr Lamba).

Address for reprints: Gilbert J. Burckart, PharmD, FCP, University of Southern California, 1985 Zonal Avenue, PSC-100, Los Angeles, CA 90033-1086.

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The genetic polymorphisms in the ABCB1 gene, which encodes for the membrane pump, P-glycoprotein, have been previously demonstrated to have an association with tacrolimus dosing in organ transplant patients. This study associated the haplotype and genotype for ABCB1 G2677T and C3435T variants with a sequential analysis of tacrolimus blood level (ng/mL) per mg/day dosage ([L/D]) administered to 91 adult lung transplant patients at 1, 3, 6, 9, and 12 months after transplantation. Haplotype 22 carriers had a significantly higher tacrolimus [L/D] value in comparison with nonhaplotype 22 carriers (P = .04) only at 1 month after transplant. Sequential analysis demonstrated that ABCB1 genotypes 00 and 01 had low tacrolimus [L/D] values at 1 and 3 months, but these values increased substantially at 6, 9, and 12 months after transplantation. This was not true of the other genotypes with the exception of genotypes 10 and 21, which had small numbers of patients but had consistently low tacrolimus [L/D]. Haplotype analysis also suggested that the homozygous for ABCB1 2677 variant allele had more of an impact on tacrolimus [L/D] in haplotype analysis than that of ABCB1 3435. In conclusion, sequential analysis of tacrolimus [L/D] with haplotypes can explain previous clinical observations of changes in tacrolimus dosage over time but suggests that this effect is limited to individual patient haplotypes. Sequential analysis of drug dosing and haplotypes relationships can provide important information about the induction or inhibition of drug-drug and disease-drug interactions among specific haplotypes.

Key Words: P-glycoprotein • ABCB1 • polymorphism • haplotype • transplantation • tacrolimus dosing

Our research and the studies of others have focused on the potential role of ABCB1 gene polymorphisms on tacrolimus dosing.^1,2 However, the impact of ABCB1 gene polymorphisms on P-gp activity is controversial. Both increased and decreased P-gp function has been associated with the synonymous ABCB1 C3435T gene polymorphism^3-6 as well as with the nonsynonymous ABCB1 G2677T gene polymorphism.^4,7,8 These conflicting reports suggest the possibility that many gene polymorphisms in linkage disequilibrium rather than as single-nucleotide polymorphisms (SNPs) may control P-gp function and drug response.

One of possible reasons for these contradictory findings is that the investigators failed to consider ABCB1 haplotypes. One retrospective study on 81 renal transplant recipients indicated that the ABCB1 exon 21 SNP correlated significantly with the daily tacrolimus dose and concentration/dose ratio, and it further found that the haplotype analysis of the exon 21 and 26 SNPs were associated with tacrolimus dose requirements.⁹ However, Haufroid et al¹⁰ failed to demonstrate any effect of ABCB1 haplotypes on tacrolimus dosing after transplantation in renal transplant patients at a discreet time point. Johne et al¹¹ recently suggested that the combination of ABCB1 SNP variants into haplotypes might be of higher value in predicting P-gp activity.

We have previously observed that specific genotypes of ABCB1 in pediatric heart transplant patients require significantly larger tacrolimus doses to maintain their tacrolimus blood concentration.² In contrast, in a study in adult lung transplant patients published in the Journal of Clinical Pharmacology,¹² we found no effect of ABCB1 SNPs on tacrolimus dosing. Given the question of the effect of ABCB1 haplotypes on immunosuppressive drug dosing and the absence of any information related to the stability of this effect over time, the objective of this analysis was to reexamine the effect of the ABCB1 gene haplotypes in predicting changes in tacrolimus dosing as a sequential assessment of tacrolimus dosing over the first year posttransplantation in this same adult lung transplant patient population.

	PATIENTS AND METHODS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Adult lung transplant recipients who had been maintained on tacrolimus-based immunosuppressive therapy were included in this study. The protocol was approved by the Institutional Review Board of the University of Pittsburgh, and informed consent was obtained in all living patients. A sample of 3 to 7 mL anticoagulated venous blood was obtained from each patient, and DNA was extracted from whole blood using a standard phenol/chloroform procedure.

Patient records were reviewed, and only patients who had been treated from the time of transplantation with tacrolimus and prednisone-based immunosuppression were included in this study. No attempts were made to wean corticosteroid therapy. Patients were only included if 12 months of follow-up information was available and were excluded if they were on other known inducers or inhibitors of CYP3A or P-glycoprotein. Tacrolimus steady-state trough blood concentrations, collected as trough samples approximately 12 hours after the last tacrolimus dose, were recorded at 1, 3, 6, 9, and 12 months posttransplantation. The tacrolimus blood level (ng/mL) per dose (mg/day) at 1, 3, 6, 9, and 12 months after lung transplantation was calculated for each patient and expressed as [L/D]. Tacrolimus blood concentrations were assayed in whole blood by the Abbott IMx system (Abbott Diagnostics Division, Abbott Park, Ill).

Polymorphism Identification for MDR1 C3435T and G2677T Genotypes
Sequencing of MDR1 G2677T. The polymerase chain reaction (PCR) amplification of the MDR1 G2677T gene fragment was carried out using the forward primer 5'-GCAGGCTATAGGTTCCAGGCT-3', which anneals at position 65440 (Genbank no. AC005068 [GenBank] ), and the reverse primer 5'-TGAGGAATGGTTATAAACACAT-3' anneals at position 65137 (Genbank no. AC005068 [GenBank] ). Polymerase chain reaction was carried out in a total volume of 50 µL using 50 ng of genomic DNA, 5 pmol of each forward and reverse primer, 0.2 mM dNTP (Promega), 1x PCR buffer, and 1.75 units of Hifidelity Taq DNA polymerase (Expand High Fidelity PCR system, cat. no. 1 732 650, Roche). The PCR process included initial denaturation at 92°C for 5 minutes followed by 35 cycles of denaturation at 92°C for 30 seconds, annealing at 55°C for 30 seconds and synthesis at 72°C for 1 minute. The final elongation was carried out for 5 minutes at 72°C. The unincorporated nucleotides and primers were removed by incubation with shrimp alkaline phosphatase and exonuclease I (USB Corporation, Cleveland, Ohio) for 30 minutes at 37°C followed by enzyme inactivation at 80°C for 15 minutes prior to sequencing. Sequencing was carried out on an ABI Prism 3700 Automated Sequencer using the PCR primers.

Sequencing of MDR1 C3435T. The amplification of the MDR1 C3435T gene was carried out using forward primer 5'-TCACAGTAACTTGGCAGTTTCAG-3', which anneals at position 43500 (Genbank no. AC005068 [GenBank] ), and the reverse primer 5'-ACTATAGGCCAGAGAGGCTG-3' anneals at position 43174 (Genbank no. AC005068 [GenBank] ). Polymerase chain reaction was carried out as for G2677T with annealing at 59°C. The unincorporated nucleotides and primers were removed as described above. Sequencing was carried out on ABI Prism 3700 Automated Sequencer using the PCR primers.

Sequence analysis. Sequences were assembled using the Polyphred package (University of Washington, Seattle). This program automatically detects the presence of heterozygous SNP substitutions by fluorescence-based sequencing of PCR products.^5,6

Genotypes and Haplotypes
Haplotype analysis was restricted to SNPs C3435T and G2677T on the basis of the linkage disequilibrium observed between both positions. Each genotype was assigned to haplotype pairs. For those individuals who were homozygous at both variants or who were heterozygous at only 1 variant, the haplotypes could be assigned unambiguously. With the assumption that each haplotype is dominantly inherited, comparisons were performed between carriers of one particular haplotype and noncarriers of that haplotype. ABCB1 haplotypes and genotypes derived from SNPs G2677T and C3435T are shown in Table I.

Statistical Analysis
One-way analysis of variance (ANOVA) was used to detect the differences in tacrolimus [L/D] among the sequential time points within the patients with the same genotype or among the patients with different genotypes on each certain time point. The Bonferroni multiple-comparison test was used to detect significant differences between the each pair. The t test assuming unequal variances was used for the comparison of 2 groups. A P value of .05 was considered statistically significant. All of the values were presented as an arithmetic mean and 95% confidence interval or mean ± SD. Statistics were calculated with Prism software (Version 4, GraphPad Software Inc, San Diego, Calif).

	RESULTS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Ninety-one patients were assessed for ABCB1 genotypes. Ninety patients were white, and 1 was African American. Due to technical problems or limitation in DNA availability, either ABCB1 C3435T or G2677T genotyping, but not both, was not available in 10 of these 91 patients, so that a total 81 patients were involved in the haplotyping study. These 81 patients were involved in our earlier study.¹² Patients were grouped according to the SNP genotype and haplotype (Table I) to explore the influence of the genotypes and haplotypes on the tacrolimus [L/D]. The demographic characteristics of the patient population by genotype and haplotype are listed in Table II.

ABCB1 Exon 26/21 Single-Nucleotide Polymorphisms and Tacrolimus [L/D]
Of the 81 patients, 28 were homozygous wild-type exon 21 2677G and 23 homozygous 2677T. Thirty patients were heterozygous G2677T carriers. For exon 26 C3435T, 21 were homozygous wild type, and 35 and 25 were heterozygous and homozygous variant carriers, respectively. The frequencies of SNPs exon 21 G2677T and 26 C3435T in this study were consistent with previous findings.¹³ A comparison of the frequencies is listed in Table III.

Patients homozygous for the ABCB1 exon 21 2677G have a significantly lower tacrolimus [L/D] value in comparison with heterozygous G2677T (P = .04, t test) at 1 month posttransplant. To exclude its potential confounding influence on the association between ABCB1 G2677T polymorphism and tacrolimus level, CYP3A5 polymorphism was assessed between ABCB1 2677G homozygous and G2677T heterozygous genotypes. Three out of 28 patients (10.7%) who are ABCB1 exon 21 GG genotype are in the CYP3A5 ^*1/^*1 and ^*1/^*3 genotype group, whereas 3 out of 30 patients (10%) who are in ABCB1 exon 21 GT genotype are CYP3A5 ^*1/^*3 genotype carriers (P = .93, ² test). Other SNPs provided no significant association with the tacrolimus [L/D] value in this study patient population (Table IV).

Genotypes and Haplotypes with Tacrolimus [L/D]
Haplotype analysis was based on the linkage disequilibrium and previous study published by Johne et al.¹¹ Basically, different allelic combinations of both G2677T and C3435T variants can theoretically lead to 4 theoretically different haplotypes and 9 possible genotypes (Table I). All of the haplotypes but not all of the genotypes were found in this study population. The most frequent genotypes were genotype 00, 11, and 22 and occurred in 24.7%, 29.6%, and 24.7% of the study population, respectively. Genotypes 10 and 21 are rare and only occurred in 1.2% and 3.7% of the patients, respectively. Genotypes 02 and 20 did not occur in this study population. Haplotypes 11 and 22 were the most common and occurred in 45.1% and 44.4% of the patients, respectively. Haplotypes 12 and 21 were rare, with frequencies of 8.1% and 2.4%, respectively. These frequencies indicate that genotype 11 is more likely represented by haplotype pair 11/22 than the rare 12/21, which is consistent with that calculated previously from a random sample of 687 subjects.¹¹

Haplotype 22 carriers had a significantly higher tacrolimus [L/D] value in comparison with nonhaplotype 22 carriers (P = .04, t test) at 1 month posttransplant. To exclude the potential confounding influence on the association between ABCB1 haplotype 22 and tacrolimus level, CYP3A5 polymorphism was assessed between haplotype 22 and non-22 patients. Six out of 52 patients (11.5%) who are haplotype 22 are in the CYP3A5 ^*1/^*1 and ^*1/^*3 genotype group, whereas 3 out of 29 patients (10.3%) who are haplotype non-22 are in the CYP3A5 ^*1/^*3 genotype group (P = .87, ² test). No significant difference between haplotype 22 and non-22 patients on tacrolimus [L/D] was observed at other time points. The number of haplotype 21 carriers was small, but differences were observed at 3 and 9 months posttransplantation between the haplotype 21 carrier and non-21 carriers (P < .05, t test). Other genotype and haplotype groups did not demonstrate significant differences in tacrolimus [L/D] value for the 5 time points. None of the haplotype groups demonstrated a significant association with tacrolimus [L/D] among the sequential time points (ANOVA with Bonferroni multiple-comparison test) (Table IV).

Looking at the sequential change in mean tacrolimus [L/D] over the 12 months after transplantation, several differences among the genotypes and haplotypes can be observed. Consistent with previous SNP observations in the ABCB1 2677 GG and 3435 CC patients, the tacrolimus [L/D] in genotypes 00 and 01 is very low initially in the posttransplantation period in comparison to the other genotypes. By 6 months, however, the tacrolimus [L/D] in these genotypes is very much like the other genotypes, which indicates a change in drug disposition in patients with genotypes 00 and 01 in comparison to other genotypes. Genotypes 10 and 21 also have a very low tacrolimus [L/D], but the patient numbers are very small (n = 1 and n = 3, respectively). In genotypes 10 and 21, the low tacrolimus [L/D] changes very little over the first 9 to 12 months after transplantation.

Although genotype 00 reflects the ABCB1 wild type for both G2677T and C3435T, genotype 01 represents the heterozygous state for ABCB1 3435 and yet still has the same tacrolimus [L/D]. The converse situation is genotype 10, where ABCB1 3435 is homozygous wild type and 2677 is heterozygous. Genotype 10 had only 1 patient observation, but the tacrolimus [L/D] was equally as low as the genotype 00 and 01 patients until 12 months after transplantation.

	DISCUSSION

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Haplotyping studies for ABCB1 can help to clarify some of the previous observations of ABCB1 genotype-phenotype relationships that were previously contradictory. Controversy remains about the association between ABCB1 genetic variation, P-gp expression and function, and concentrations in the plasma of various substrates of P-gp.¹⁴ In the study by Hoffmeyer and colleagues,³ the ABCB1 3435 TT genotype was associated with low P-gp expression in enterocytes and high concentrations in the plasma of digoxin. However, in a study by Kim and colleagues,⁴ the ABCB1 3435 TT genotype (in the context of a C1236T, G2677T haplotype) was associated with low concentrations in the plasma of the P-gp substrate fexofenadine. Fellay and colleagues⁵ found that the ABCB1 3435 TT genotype was associated with low expression of the ABCB1 transcript and P-gp in peripheral blood mononuclear cells, as well as with low concentrations in the plasma of nelfinavir and efavirenz. Because C3435T and G2677T are closely linked,^7,15 the net contribution of the polymorphisms of the human ABCB1 gene on the pharmacokinetic profiles of substrates of P-gp is difficult to determine during therapeutic treatment.

The ongoing identification of SNPs will contribute to the identification of gene variants related to disease process and response to medications. However, genotyping of individual SNPs alone may not always provide enough information to reach these goals, which necessitates having knowledge of the haplotype structure of SNPs over genomic distances of several kilobases. Individual polymorphisms located closely together on a chromosome and in strong linkage dis-equilibrium are inherited together as a unit referred to as a haplotype. These haplotypes, through their proximity to a causative SNP, may themselves have no effect on drug response but rather act as markers of the underlying cause of the drug response. The evaluation of haplotypes across candidate gene regions will allow the identification of associations between genes and drug response without requiring the discovery of the causative variants first. Alternatively, specific haplotypes may themselves be responsible for the variation in drug response and be a far better marker than any one of their component SNPs. Individual variants may also be present on other haplotypes, but only a specific combination is associated with disease or response to medication. This possibility has been demonstrated in a recent pharmacogenomic study carried out by Drysdale¹⁶ in which 13 variable sites within a 1.6-kb contiguous segment of ß2-adrenergic receptor gene were examined. Twelve haplotypes were identified and tested for their association with response to the anti-asthma therapy. They found that mean responses varied by more than 2-fold for different haplotype pairs. Although haplotypes were significantly related to response, the individual SNPs comprising the haplotypes were not.

Johne et al¹¹ recently suggested that the combination of certain SNP variants into haplotypes might be of higher value in predicting P-gp activity. In a prospective study, the authors were able to demonstrate significant differences in digoxin pharmacokinetics between carriers and noncarriers of haplotype 12 (2677G/3435T), with substantially increased AUC_0-4 and C_max values of orally administered digoxin. However, there have been conflicting reports, such as the one by Mai et al.¹⁷ In this study, the authors concluded that the ABCB1 haplotypes derived from the SNPs G2677T on exon 21 and C3435T on exon 26 are not associated with CsA pharmacokinetics in renal transplant patients. In the present study, we tested whether ABCB1 haplotypes derived from SNPs 2677G>T and 3435C>T could explain the large interindividual differences in tacrolimus blood concentrations in lung allograft recipients, as well as whether the haplotypes derived from ABCB1 exon 21 G2677T and exon 26 C3435T genotypes are better predictors than individual SNPs. Four different haplotypes and 7 different genotypes were found in the study population, and the observed frequencies of SNP variants, genotypes, and haplotypes were consistent with those reported for large random samples.^11,13,18

Chowbay et al¹⁹ recently studied the influence of ABCB1 haplotypes on CsA disposition in heart transplant recipients. They found that CsA exposure (AUC_{0-4 h}, AUC_{0-12 h},C_max) was not significantly different by genotypes at exons 12, 21, and 26 or by haplotypes. Accordingly, the studies from Johne et al¹¹ and Chowbay et al¹⁹ further emphasize the importance of assessing haplotypes in ABCB1 if meaningful genotype-phenotype correlations are to be determined in transplant patients.

In our study, several observations are important but are marginalized by the small number of subjects with a particular genotype. Haplotyping may allow us to indirectly examine the comparative function of exon 21 and exon 26 because the importance of exon 26 as a synonymous polymorphism has been questioned. If genotype 12, where exon 26 is homozygous variant, is compared with genotype 21, where exon 21 is homozygous variant, an interesting difference in the mean values for the tacrolimus [L/D] is observed. At each time point after transplantation, the genotype 12 [L/D] is 3 to 5 times greater than the [L/D] for the genotype 21 patients (see Table IV). If this observation is confirmed in a larger numbers of patients, it would be possible to conclude that having a homozygous ABCB1 2677 TT genotype has a much greater impact on the tacrolimus dosage requirement than does having a ABCB1 3435 TT genotype. A larger number of patients might also clarify the observation that graft survival in genotype 12 was approximately 50% of that in genotype 21.

Another important observation is the change in tacrolimus [L/D] over the time course of the first year after transplantation. Because tacrolimus was initially used in transplantation, clinicians have recognized that patients who are many months posttransplantation require less drug to achieve the same blood tacrolimus levels as earlier in the postoperative period.²⁰ However, this is not a consistent finding among patients. The current analysis suggests that the nonhaplotype 22 carriers (2677T-T3435) are the patient population that has led to this observation because the mean value of the tacrolimus [L/D] at 1 and 3 months post transplantation is only approximately 50% of the [L/D] at 6, 9, and 12 months posttransplantation. This would indicate that the nonhaplotype 22 carriers require much more tacrolimus to achieve the desired tacrolimus concentrations at 1 and 3 months than they do at a later time period. In contrast to this, the mean tacrolimus [L/D] for the haplotype 22 carriers was stable over the 12-month postoperative period. This time-dependent genetic effect would have to assume that other changes in the transplant patient (eg, cytokine production) affect protein or mRNA stability and degradation.

Several studies have found an association between tacrolimus dosing and SNPs for either ABCB1 or the drug-metabolizing enzyme CYP3A5. Although our haplotype analysis did not improve our ability to predict tacrolimus [L/D] in adult lung transplant patients over the first year posttransplantation, we were able to distinguish differential changes over time in tacrolimus [L/D] between genotypes and haplotype carriers that may have important implications for individualizing immunosuppressive therapy. Larger numbers of transplant patients will be needed to confirm these preliminary observations, but sequential analysis of drug dosing in relation to haplotypes can provide important information about the induction or inhibition of drug-drug and disease-drug interactions.

DOI: 10.1177/0091270005274507

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. 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: 1486-1489.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

2. 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: 477-483.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms 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: 3473-3478.[Abstract/Free Full Text]

4. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70: 189-199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study [comment]. Lancet. 2002;359: 30-36.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res. 2001;18: 1400-1404.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther. 2001;297: 1137-1143.[Abstract/Free Full Text]

8. Drescher S, Schaeffeler E, Hitzl M, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol. 2002;53: 526-534.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Anglicheau DVC, Laurent-Puig P, Becquemont L, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol. 2003;14: 1889-1896.[Abstract/Free Full Text]

10. Haufroid VMM, Van Kerckhove V, Wawrzniak J, et al. The effect of CYP3A5 andMDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14: 147-154.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Johne A, Kopke K, Gerloff T, et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther. 2002;72: 584-594.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004;44: 135-140.[Abstract/Free Full Text]

13. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69: 169-174.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Kim RB. MDR1 single nucleotide polymorphisms: multiplicity of haplotypes and functional consequences. Pharmacogenetics. 2002;12: 425-427.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Zheng H, Webber S, Zeevi A, et al. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Human Immunol. 2002;63: 765-770.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

16. Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA. 2000;97: 10483-10488.[Abstract/Free Full Text]

17. Mai I, Goldammer M, Johne A, Kruger H, Budde K, Roots I. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol. 2003;43: 1101-1107.[Abstract/Free Full Text]

18. Ameyaw MM, Regateiro F, Li T, et al.. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001;11: 217-221.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

19. Chowbay BCS, Cheung YB, Zhou Q, Lee EJD. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics. 2003;13: 89-95.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Pou L, Brunet M, Bilbao I, et al. Therapeutic drug monitoring of tacrolimus in liver transplantation, phase III FK506 multicenter Spanish Study Group: a two-year follow-up. Ther Drug Monitor. 1998;20: 602-606.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Zheng, H. Articles by Burckart, G. J. Search for Related Content PubMed PubMed Citation Articles by Zheng, H. Articles by Burckart, G. J. Social Bookmarking                   What's this?