Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients

Takafumi Kuzuya, Takaaki Kobayashi, Natsuko Moriyama, Takaharu Nagasaka, Itsuo Yokoyama, Kazuharu Uchida, Akimasa Nakao, Toshitaka Nabeshima

Research output: Contribution to journalArticle

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Abstract

Background. Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. Methods. The area under the time-concentration curve from 0 to 2 hr (AUC0-2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. Results. No association was found between polymorphisms in the MDR1 and CsA AUC0-2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0-2/dose/kg (706.2 μg·hr/L to 819.2 μg·hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. Conclusions. There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.

Original languageEnglish
Pages (from-to)865-868
Number of pages4
JournalTransplantation
Volume76
Issue number5
DOIs
Publication statusPublished - 15-09-2003
Externally publishedYes

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Amlodipine
Cyclosporine
Pharmacokinetics
Kidney
P-Glycoprotein
Transplant Recipients
Immunosuppressive Agents
Restriction Fragment Length Polymorphisms
Biological Availability

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Kuzuya, Takafumi ; Kobayashi, Takaaki ; Moriyama, Natsuko ; Nagasaka, Takaharu ; Yokoyama, Itsuo ; Uchida, Kazuharu ; Nakao, Akimasa ; Nabeshima, Toshitaka. / Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. In: Transplantation. 2003 ; Vol. 76, No. 5. pp. 865-868.
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abstract = "Background. Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. Methods. The area under the time-concentration curve from 0 to 2 hr (AUC0-2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. Results. No association was found between polymorphisms in the MDR1 and CsA AUC0-2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0-2/dose/kg (706.2 μg·hr/L to 819.2 μg·hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. Conclusions. There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.",
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Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. / Kuzuya, Takafumi; Kobayashi, Takaaki; Moriyama, Natsuko; Nagasaka, Takaharu; Yokoyama, Itsuo; Uchida, Kazuharu; Nakao, Akimasa; Nabeshima, Toshitaka.

In: Transplantation, Vol. 76, No. 5, 15.09.2003, p. 865-868.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients

AU - Kuzuya, Takafumi

AU - Kobayashi, Takaaki

AU - Moriyama, Natsuko

AU - Nagasaka, Takaharu

AU - Yokoyama, Itsuo

AU - Uchida, Kazuharu

AU - Nakao, Akimasa

AU - Nabeshima, Toshitaka

PY - 2003/9/15

Y1 - 2003/9/15

N2 - Background. Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. Methods. The area under the time-concentration curve from 0 to 2 hr (AUC0-2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. Results. No association was found between polymorphisms in the MDR1 and CsA AUC0-2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0-2/dose/kg (706.2 μg·hr/L to 819.2 μg·hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. Conclusions. There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.

AB - Background. Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. Methods. The area under the time-concentration curve from 0 to 2 hr (AUC0-2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. Results. No association was found between polymorphisms in the MDR1 and CsA AUC0-2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0-2/dose/kg (706.2 μg·hr/L to 819.2 μg·hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. Conclusions. There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.

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