Clinical and Experimental Pharmacology and Physiology (2006) 33, 10931098

doi: 10.1111/j.1440-1681.2006.04492.x

Original
Blackwell
Publishing
Asia
Y-F
Cyclosporine
Hu etArticle
al.
pharmacogenetics

EFFECTS OF GENETIC POLYMORPHISMS OF CYP3A4, CYP3A5

AND MDR1 ON CYCLOSPORINE PHARMACOKINETICS AFTER
RENAL TRANSPLANTATION
Yong-Fang Hu,* Wen Qiu, Zhao-Qian Liu, Li-Jun Zhu, Zhong-Qi Liu,* Jiang-Hua Tu,
Dan Wang, Zhi Li, Jun He, Gan-Ping Zhong, Gan Zhou* and Hong-Hao Zhou

*Peking University Third Hospital, Beijing, Pharmacogenetics Research Institute, Institute of Clinical Pharmacology,
Central South University, The Third Affiliated Xiangya Hospital of Central South University, Changsha, Hunan and

The Second Affiliated Hospital of Lanzhou Medical College, Lanzhou, Gansu, PR China

SUMMARY
1. The calcineurin inhibitor cyclosporine is widely used to
prevent allograft rejection after solid organ transplantation.
It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual
differences in the activity and expression of the metabolising
enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug
efflux pump P-glycoprotein (P-gp) contribute considerably
to cyclosporine pharmacokinetics. Variability in the activity of
CYP3A4, CYP3A5 and P-gp could be considered to result from
genetic polymorphisms encoding their genes.
2. The aim of the present study was to evaluate retrospectively
the effects of genetic polymorphisms of CYP3A4, CYP3A5 and
MDR1 on cyclosporine dose adjusted trough blood concentration
during the early period after renal transplantation in Chinese
patients.
3. One hundred and six renal transplant recipients in
China were genotyped by polymerase chain reactionrestriction
fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and
MDR1 C3435T. Cyclosporine whole blood levels were measured
by fluorescence polarization immunoassay. Dose-adjusted trough
blood concentrations (C0) were determined and compared among
the different genotype groups.
4. The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1
C3435T variant alleles were 0.005 (95% confidence interval
(CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95%
CI 0.526, 0.531), respectively, and these alleles exhibited
incomplete linkage disequilibrium. The median cyclosporine
dose-adjusted C0 in CYP3A5*1/*1 genotype subjects (n = 6) was
14.8 ng /mL per mg per kg (range 11.126.8 ng /mL per mg per kg),
in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng /mL per mg per kg
(range 9.0 61.0 ng/mL per mg per kg) and for CYP3A5*3/*3
patients (n = 66) it was 26.4 ng/mL per mg per kg (range
9.885.8 ng/mL per mg per kg; P = 0.012, KruskalWallis test).
Correspondence: Professor Hong-Hao Zhou, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, PR China.
Email: hhzhou@public.cs.hn.cn
Received 25 February 2005; revision 16 April 2006; accepted 23 April 2006.
2006 The Authors
Journal compilation 2006 Blackwell Publishing Asia Pty Ltd

Accordingly, cyclosporine dose-adjusted C0 was larger in CYP3A5

non-expressors than expressors in the first week after renal
transplantation. In addition, wild-type homozygotes (n = 21) for
MDR1 C3435T had a slight but significantly lower dose-adjusted
C0 compared with heterozygotes (n = 58): 17.7 (10.360.8) versus
26.4 (9.067.3) ng/mL per mg per kg, respectively (P = 0.014,
MannWhitney U-test).
5. In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large
interindividual variability of cyclosporine pharmacokinetics
during the early phase after renal transplantation in Chinese
patients. Patients with the CYP3A5*3 variant genotype require
a low dose of cyclosporine to reach target levels compared with
those with the CYP3A5*1 allele.
Key words: Chinese, cyclosporine, CYP3A4, CYP3A5, MDR1
(ABCB1), polymorphisms, transplantation.

INTRODUCTION
Cyclosporine (International Nonproprietary Names (INN); ciclosporin)
is a calcineurin inhibitor widely used to prevent acute rejection
after solid organ transplantation. However, cyclosporine has low oral
bioavailability, a very narrow therapeutic index and shows marked
interindividual differences in its pharmacokinetics. It is important to
determine the initial optimal dose of cyclosporine so as to a achieve
target concentration range during the early phase after organ transplantation. At present, periodic monitoring of cyclosporine blood
concentrations is required in renal transplant patients in order to
maintain cyclosporine levels so as to achieve the target concentration
range and to reduce the risk of serious adverse reactions, such as
over- and underimmunosuppression. The predose, or trough, is widely
used as a pharmacokinetic parameter for therapeutic drug monitoring
of calcineurin inhibitors.13
The cytochrome P450 (CYP) 3A subfamily is responsible for
the metabolism of approximately 50% of drugs and endogenous
substances, such as the calcineurin inhibitor. The CYP3A subfamily
consists of various isozymes, including CYP3A4, CYP3A5, CYP3A7
and CYP3A43.47 P-Glycoprotein (P-gp) is one of the multidrug
resistance-related proteins and is encoded by the multidrug resistance
1 (MDR-1) gene. P-Glycoprotein is found throughout the body,
in the small intestine, liver, kidney, adrenal glands and pancreas. It
is expressed at the apical surface of the membrane in the small intestine,

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Y-F Hu et al.

where it prevents the absorption of possibly toxic xenobiotics from

the intestinal lumen.8 Cyclosporine is also a substrate for P-gp. Recently,
some studies have shown that CYP3A4, CYP3A5 and P-gp in the
human intestine and liver can contribute to inter- and intra-individual
differences in the pharmacokinetics of calcineurin inhibitors.9,10
Moreover, recent advances in pharmacogenomics research have determined that sequence variations of genes encoding drug-metabolising
enzymes and/or drug transporters may explain, in part, differences
in their protein expression levels and activities.11,12
A number of single nucleotide polymorphisms (SNP) of CYP3A5,
CYP3A4 and MDR1 have been identified in recent years.1319 Recently,
the CYP3A4*18A allele was found in the Chinese population20 and
showed significantly higher turnover numbers for both testosterone
and insecticide chlorpyrifos in vitro. Thus, CYP3A4*18A could
increase the activity of CYP3A4.15 However, the functional significance of CYP3A4*18A in drug metabolism has not been clarified
in vivo. Moreover, the CYP3A5*3 polymorphism was found to cause
alternative splicing and protein truncation, resulting in the absence
of a functional CYP3A5 gene in hepatic and intestinal tissue.21 The
CYP3A5*1 allele is necessary for the production of a fully catalytic
CYP3A5 protein and also influences the ratio of the expression level
of CYP3A4 and CYP3A5 proteins. The variant allele of the MDR1
gene is located in exon 26 in a wobble position and was found to
be associated with lower P-gp function.8 Accordingly, some recent
studies have explored a relationship between genetic polymorphisms
in CYP3A5*3 and MDR1 C3435T and the dose requirements of
cyclosporine in either in stable organ transplant patients or healthy
subjects. However, there are some discrepancies in the reported
associations between genetic polymorphisms in CYP3A4, CYP3A5
and MDR1 and individual cyclosporine pharmacokinetics.2227 In
addition, most studies have reported data that focused mainly on
Caucasian transplant recipients and there are few data regarding
cyclosporine pharmacokinetics in Chinese patients.
For renal transplant patients, achieving target blood concentrations
of cyclosporine as soon as possible after transplantation is key in
the prevention of rejection.28,29 However, it should also be noted that
in the early phase after transplantation, several external factors may
have a significant effect on cyclosporine pharmacokinetics. Moreover,
there are no published reports indicating that genetic polymorphisms
in CYP3A4, CYP3A5 and MDR1 are associated with cyclosporine
dose requirements immediately after renal transplantation. The impact
of mutations on the enzymes and transporters involved in cyclosporine
disposition in the early phase after transplantation remain unknown.
Conversely, the frequencies of variant alleles of CYP3A5*3 and
MDR1 C343T and cyclosporine dose requirements differ significantly
among various ethnic groups. Some studies have shown that there
are marked interindividual and interethnic differences in cyclosporine
pharmacokinetics.30,31
The aim of the present study was to determine the relationship
between genetic polymorphisms in CYP3A4, CYP3A5 and MDR1 and
cyclosporine pharmacokinetics in the early phase after transplantation in Chinese patients.

METHODS
Population
One hundred and six renal transplant patients from the Second Affiliated
Hospital of Lanzhou Medical College (Lanzhou, Gansu, PR China) and the

Third Affiliated Xiangya Hospital of Central South University (Changsha,

Hunan, PR China) who underwent transplantation between June 2001 and
April 2004 were invited to participate in the present retrospective study.
Each patient had been treated from the time of transplantation with cyclosporine and was maintained on a triple immunosuppressive regimen consisting of cyclosporine, mycophenolate mofetil and sterioids. Patients for
whom follow-up information was available at 1 week after transplantation and
in whom the cyclosporine trough blood concentration (C0) was determined
within 1 week after transplantation were included in the study. In addition,
patients included in the study had not taken any medication known to affect
cyclosporine pharmacokinetics, including CYP3A inducers and inhibitors
(e.g. verapamil, erythromycin, clarithromycin, ketoconazole, fluconazole and
sulphadimidine/trimethoprim).
Cyclosporine microemulsion was given in two equal doses: the morning
dose was administered after blood sampling for trough determination and
the last dose was administered in the evening 12 h after a the morning dose.
A commonly used steroid-tapering schedule was followed (500 mg of i.v.
methylprednisolone at the time of surgery, 125 mg of i.v. methylprednisolone
the following day and then 20 mg oral prednisolone daily, progressively
tapered to 5 mg daily at 3 months after transplantation). Cyclosporine dose
and blood concentrations, as well as demographic and clinical data, were
obtained at 7 5 days after transplantation. Patient characteristics are given
in Table 1.
The study was performed in accordance with the Declaration of Helsinki
and amendments. The protocol was approved by the Ethics Committee of
Central South University Xiangya School of Medicine and written informed
consent was obtained from all participants.
During routine visits, 1 mL venous blood was drawn into a sterile tube
containing EDTA and blood samples were then stored at -80C until the
isolation of genomic DNA for genotyping.

Determination of cyclosporine whole blood

concentrations
Cyclosporine whole blood levels were quantified using a monoclonal fluorescence polarization immunoassay run on a TDx analyser according to the
manufacturers instructions (Abbott Laboratories, Chicago, IL, USA). The
assay was calibrated with manufacturer-supplied regents and verified
daily by analysis of quality control samples with expected concentrations
in the low (120180 mg /L), median (340460 mg /L) or high (680920 mg/L)
range. The inter- and intraday variabilities were less than 4% over the
concentration range 150800 mg /L. The limit of detection was 25 mg/L.

Isolation and genotype analysis of DNA

Genomic DNA was isolated from the 0.5 mL EDTA-treated whole blood
using a standard phenolchloroform extraction method.32
Polymerase chain reactionrestrict fragment length polymorphism (PCRRFLP) was performed to genotype CYP3A5 at intron 36986 A > G and
MDR1 at exon 26. The C3435T SNP with only slight modifications were
compared with those described previously.33,34
Details of the primer sequences, amplification lengths and restriction
enzymes used are given in Table 2. In brief, the PCR assay was performed
in a 25 mL reaction system. The PCR products for CYP3A5 and MDR1 were
digested by the restriction enzymes Ssp and Sau3A (Takara Shuzo, Tokyo,
Japan) in a total volume of 15 mL for 4 h and 10 mL for 2 h at 37C. The
digested products were separated on a 4 and 2% agarose gel, respectively.
For CYP3A5, two samples of each different genotype were sequenced to confirm the expected sequences of each genotype. Sequencing was performed
using the primers 3A5F (5-CTTCAATTTTTCACTGACCTAATATTC-3)
and 3A5R (5-ATCCATACCCCTAGTTGT ACGACAC-3).
To determine the genotype of CYP3A4A at exon 10, primer design sequence
data from GeneBank (Accession no. NG_000004) were used and the primer
sequences, fragment sizes and restriction enzyme used are listed in Table 2.
The PCR amplifications were performed in a total volume of 25 mL, comprising 2.5 mL of 10 PCR buffer, 40 pmol/L each primer, 0.2 mmol/L each
dNTP, 1.5 U Taq DNA polymerase (Takara Shuzo) and 100 ng genomic DNA

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Cyclosporine pharmacogenetics
Table 1 Demographic and clinical characteristics of Chinese renal transplant patients
Demographics

Age (years)
Gender
No. women
No. men

41.8 11.8, 40 (16 71)

34
72

Bodyweight (kg)
Cyclosporine dose (mg/day)
Creatinine ( mmol/L)
Cause of end-stage renal disease
Hypertension
Diabetes mellitus
Glomerulonephritis
Hepatitis
Other

57.7 9.9, 56.5 (38 89)

348 59, 350 (205 600)
108 37, 130 (53.8 290)
39
25
19
2
21

Cadaveric/live donor
Transplant number (1/2)
Frequency of the MDR1 C3435T variant allele
Frequency of the CC genotype
Frequency of the CG genotype
Frequency of the GG genotype

98/5
98/8
21
58
27

0.528
0.198
0.547
0.254

Frequency of the CYP3A5*3

Frequency of the *1/*1 genotype
Frequency of the *1/*3 genotype
Frequency of the *3/*3 genotype

6
34
66

0.783
0.057
0.321
0.623

Frequency of the CYP3A4*18A

Frequency of the *1*1 genotype
Frequency of the *1/*18 genotype

105
1

0.005
0.991
0.009

Where appropriate, data are given as the meanSD, followed by the median with the range given in parentheses.

Table 2 Polymerase chain reactionrestriction fragment length polymorphism genotyping for the CYP3A4, CYP3A5 and MDR1 genes
SNP

Primer sequence

Restriction enzyme

CYP3A4 exon 10
878T > C

Forward 5-AATGATTTGCCTTATTCTGGTTCTG-3
Reverse 5-TTTCACCTCCTCCCTCCTTCTC-3

HpaII

388

CYP3A5 intron 3
6986 A > G

Forward 5-CATGACTTAGTAGACAGATGAC-3
Reverse 5-GGTCCAAACAGGGAAGAAATA-3

SspI

293

MDR1 exon 26
3435C > T

Forward 5-TGCTGGTCCTGAAGTTGATCTGTGAAC-3
Reverse 5-ACATTAGGCAGTGACTCGATGAAGGCA-3

Sau3AI

248

as a template. Amplification conditions involved an initial denaturation for

7 min at 94C, followed by 35 cycles of 30 s at 94C, 1 min at 58C and
1 min at 72C, with a final extension of 7 min at 72C. After PCR amplification, a 10 mL aliquot of the PCR products (388 bp) was digested for 2 h
at 37C with 10 units of Hpa (Takara Shuzo). The digested PCR products were
analysed by electrophoresis on a 3% agarose gel in the presence of ethidium
bromide. Bands of the DNA fragments were visualized under ultraviolet
light. The Hpa digestion of wild-type DNA yields a band of 388 bp. The
CYP3A4*18A variant allele creates one restriction site and Hpa digestion
yielded 199 and 189 bp fragments.

Fragment length (bp)

frequencies for the various SNP were assessed by Fishers exact test.
Ninety-five percent confidence intervals (CI) were calculated for all observed
allele frequencies. P < 0.05 was considered statistically significant. All
values are expressed as the median with the range in parentheses unless stated
otherwise. Statistical analysis was performed using spss version 11 (SPSS,
Chicago, IL, USA).

RESULTS
Frequencies of CYP3A4, CYP3A5 and MDR1 genotypes
and alleles

Statistical analysis
The MannWhitney U-test was used for the comparison of two groups and
the Kruskal Wallis test was used for the comparison of several groups.
Deviations from the HardyWeinberg equilibrium for allele and genotype

Table 1 lists the subject characteristics and the frequencies of

the variant alleles and genotypes for CYP3A4, CYP3A5 and
MDR1 in 106 Chinese renal transplant patients. The distribution

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Y-F Hu et al.

Table 3 Relationship between genetic polymorphisms of CYP3A5 and MDR1 and cyclosporine trough blood levels in 106 renal transplant patients

Genotype

Cyclosporine C0
(ng/mL)

Cyclosporine C0/dose
(ng/mL per mg per kg)

CYP3A5 intron 3 A6986G

*1/*1
*1/*3
3*/*3

66
34
6

87.7 (68.6180)
128 (58.7352)
158 (63.2522)

14.8 (11.126.8)
23.7 (9.0 61)
26.4 (9.8 85.8)

MDR1 exon 26 C3435T

C/C
C/T
T/T

21
58
27

124 (63.2402)
157 (58.7491)
143 (67.7522)

17.7 (10.3 60.8)

26.4 (9.0 67.3)
23.3 (11.185.8)

Polymorphism

Values are expressed as the median with the range given in parentheses. P < 0.05 for cyclosporine C0, 3435 C/C compared with 3435 C/T, for cyclosporine
C0/dose, CYP3A5*1/*1 compared with CYP3A5*1/*3 (MannWhitney U-test); P < 0.02 for cyclosporine C0/dose, CYP3A5*1/*1 compared with CYP3A5*3/*3
among the CYP3A5*3 and MDR1 C3435T groups (Kruakal-Wallis Test or MannWhitney U-test); P < 0.01 for cyclosporine C0 among the CYP3A5*3
group (Kruakal-Wallis test).
C0, cyclosporine trough concentration.

Fig. 1 Distribution histograms of cyclosporine trough concentrations in the

first week after renal transplantation in 106 Chinese patients.

of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T alleles

was consistent with HardyWeinberg equilibrium (each
P > 0.05).
Among the 106 patients, we found that one carried the CYP3A4*1/
*18A genotype. For the CYP3A5*3 gene, the genotype frequencies
of wild-type (*1/*1), heterozygotes (*1/*3) and variant homozygotes
(*3/*3) were 0.057 (6/106), 0.321 (34/106) and 0.623 (66/106),
respectively. For MDR1 C3435T, the wild-type genotype (C/C ) was
observed in 21 patients (19.8%), whereas 58 (54.7%) were heterozygotes (C/T ) and 27 (25.5%) were homozygotes (T/T; Table 1).

Cyclosporine trough levels in the first week after renal

transplantation
The mean cyclosporine trough concentration in the 106 patients was
172 98 ng/mL (median 145 ng/mL; range 34 522 ng/mL). There
were 15-fold differences in cyclosporine trough blood levels among
these subjects, suggesting that larger interindividual variations in
cyclosporine pharmacokinetics exist in the early phase after renal
transplantation (Fig. 1).

Fig. 2 Effect of CYP3A5 genotype on the cyclosporine dose-adjusted blood

trough concentration (C0) in the early period after renal transplantation in
106 Chinese patients. A significant difference in cyclosporine dose-adjusted
blood C0 was observed between patients with the CYP3A5*1/*1 genotype
and those carrying the CYP3A5*3 variant allele (P = 0.013, MannWhitney
U-test).

Effects of CYP3A4, CYP3A5 and MDR1 genotypes on

cyclosporine blood trough concentrations
The cyclosporine dose-adjusted blood C0 of one subjects with
the CYP3A4*1/*18A genotype was lower than that of wild-type
homozygous patients (21.1 vs 23.4 (5.685.8) ng/mL per mg per kg,
respectively).
The impact of genetic polymorphisms of CYP3A5*3 and MDR1
C3435T on cyclosporine dose-adjusted blood C0 in the early posttransplantation period in 106 renal transplant patients are summarized
in Table 3. When patients carrying the CYP3A5*1/*1 genotype
were compared with patients with the CYP3A5*3/*3 genotype,
a significant difference in cyclosporine dose-adjusted blood C0 was
observed (14.8 vs 26.4 ng/mL per mg/kg, respectively; P = 0.013,
MannWhitney U-test). As shown in Fig. 2, there was a significantly lower cyclosporine dose-adjusted blood C0 in subjects with

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Cyclosporine pharmacogenetics
the CYP3A5*1/*1 genotype compared with subjects with the
CYP3A5*1/*3 genotype (P = 0.041, MannWhitney U-test).
For MDR1 exon 26 C3435T, there was a slight and significantly
lower cyclosporine dose-adjusted C0 in wild-type homozygous (3435
C/C) patients compared with heterozygous (3435 C/T ) patients (17.7
vs 26.4 ng/mL per mg per kg, respectively; P = 0.037). No differences
were found in individuals with 3435C/C or 3435C/T compared with
patients with 3435T/T immediately after transplantation (Table 3).

DISCUSSION
It is well known that cyclosporine is metabolised primarily by
CYP3A4 and CYP3A5 in the small intestine and liver. Three main
cyclosporine metabolites, namely AM1 (hydroxylation at amino acid 1),
AM9 (hydroxylation at amino acid 9) and AM4n (N-demethylation
at amino acid 4), are produced by CYP3A4; only the AM9 metabolite
is formed by CYP3A5.35,36 Both genetic and environmental factors
are considered as causes of the the considerable interindividual
differences in CYP3A4 and CYP3A5 expression and functional
activity. Several studies have suggested that approximately 3085%
of the interindividual variability in drug disposition and response is
predominantly due to genetic factors, such as SNP.11,37 Therefore,
genetic variations in CYP3A4 and CYP3A5 may contribute to
interindividual differences in orally administered cyclosporine
pharmacokinetics.
To date, a number of SNP for CYP3A4 have been identified and
published on the Human Cytochrome P450 Allele Nomenclatute
Committee homepage (http://www.imm.ki.se/CYPalleles). However,
most SNP are rare, especially among the Chinese population, and
fail to explain completely the interindividual differences in CYP3A4
expression and functional activity. Meanwhile, CYP3A5*3, an SNP
6896 A > G, within intron 3, is strongly associated with CYP3A5
expression in adult liver and small intestine.17,21 CYP3A5 may constitute
up to 50% of total CYP3A protein in the liver and small intestine,
which carry at least one CYP3A5*1 allele.21 Saeki et al. reported
that CYP3A5*3 is a predominantly defective allele and total CYP3A
activity is correlated with CYP3A5 genotype.38 Midazolam clearance
has been reported to be significantly higher in CYP3A5*1/*1 and
CYP3A5*1/*3 samples than in CYP3A5*3/*3 samples in vitro as
well as in vivo.21,3942 Similarly, some recent studies revealed an
association between the immunosuppressant tacrolimus dose-adjusted
C0 and CYP3A5 genotype.22,24,4244
In the present study, we determined the frequencies of the
CYP3A4*18A allele, CYP3A5*3 allele and MDR1 C3435T in kidney
transplant recipients. Our findings indicate that the frequency of
both the CYP3A5*3 and MDR1 C3435T variant alleles was consistant
with previous reports.16,25 The frequency of the CYP3A4*18A
variant allele was 0.5% and this is not significantly different with
the frequnecy reported by Dai et al. in a previous study of 10 Chinese
subjects and determined by direct sequencing (2% frequency in
24 Asians).15
Moreover, we explored the effect of genetic polymorphisms of
CYP3A5 on cyclosporine dose-adjusted C0 in the early phase after
renal transplantation in Chinese patients. The findings show that
the median cyclosporine dose-adjusted C0 was significantly lower in
subjects carrying the CYP3A5*1/*1 genotype than in patients with the
CYP3A5*3/*3 genotype. This implies that the CYP3A5 polymorphism
is correlated with cyclosporine dose-adjusted C0; thus, patients
with the CYP3A5*1/*1 genotype could require a higher dose of

cyclosporine to achieve target blood concentrations than those with

the CYP3A5*3/*3 genotype immediately after renal transplantation.
In addition, cyclosporine is a substrate for P-gp. Hoffmeyer et al.45
have shown that MDR1 variant homozygotes (3435TT ) have significantly lower duodenal P-gp expression than wild-type homozygotes
and individuals with the 3435TT genotype had the highest digoxin
plasma levels, which is a substrate for P-gp. The effects of MDR1 polymorphisms on tacrolimus disposition have also been investigated.42,43
Furthermore, in the case of MDR1 at exon 26 C3435T, the present
study revealed that patients with the 3435CC genotype had lower
cyclosporine dose-adjusted C0 than patients with the 3435CT
genotype. However, a statistically significant difference was observed
between wild-type homozygous (3435CC) patients and variant
homozygous patients (3435TT ). It is possible that in the present
study population, approximately 61.5% of MDR1 C3435T variant
homozygous patients were CYP3A5 non-expressors (16 of 26 patients)
and cyclosporine C0 was markedly increased in these patients. These
results are consistent with those of a previous report.23
Although a correlation was found between the CYP3A5 genotype
and cyclosporine C0, the cyclosporine C0 showed 11-fold variations
among renal transplant recipients carrying the CYP3A5*1/*3 genotype and eightfold differences among subjects with the CYP3A5*3
variant genotype. These variations could be caused by environmental
factors, such as age, diet, disease and drugs being used concomitantly.
Meanwhile, it is of note that the cyclosporine C0 in all patients with
the CYP3A5*1/*1 genotype was lower than their target C0. In contrast,
15% of recipients with the CYP3A5*3/*3 genotype had cyclosporine
levels higher than their target C0.
In conclusion, the present study has demonstrated that genetic
polymorphisms of CYP3A5 at intron 3 are responsible, in part, for the
marked variability in cyclosporine dose-adjusted C0 during the first
week after renal transplantation in Chinese recipients. Patients with
the CYP3A5*1/*1 genotype may need to be given a higher dose of
cyclosporine to reach target concentrations compared with patients
that are CYP3A5*3 variant homozygotes. Pharmacogenetic detection
of CYP3A5 before transplantation is likely to be useful in clinical
practice to optimize the initial dose of cyclosporine administered
to individual renal transplant paitents. However, the clinical applicability
of this approach and changes in the initial dose of cyclosporine based
on the outcome of genotype screening remain to be proven.46

ACKNOWLEDGEMENTS
This work was supported by grants from the National Natural Science
Foundation of China (F30130210 and 30371668) and the China
Medical Board of New York (99-697 and 01-755).

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2006 The Authors

Journal compilation 2006 Blackwell Publishing Asia Pty Ltd