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MDR1 Haplotypes Conferring an Increased Expression of Intestinal CYP3A4 Rather than MDR1 in Female Living-Donor Liver Transplant Patients

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ABSTRACT

Purpose

This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference.

Methods

Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR.

Results

Intestinal CYP3A4 mRNA expression levels (amol/µg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92–15.2) than those with 2677GG-3435CC (3.03; range 1.38–4.68) and 2677GT-3435CT (median, 4.31; range, 0.07–9.42) (P = 0.022), but not in men (P = 0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender.

Conclusion

MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women.

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Abbreviations

C/D:

Concentration/dose

CYP:

Cytochrome P450

LDLT:

Living-donor liver transplantation

MDR:

Multidrug resistance

Pgp:

P-glycoprotein

SNP:

Single nucleotide polymorphism

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ACKNOWLEDGEMENTS

This work was supported in part by the 21st Century Center of Excellence (COE) Program “Knowledge Information Infrastructure for Genome Science”, and by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. K. Hosohata was supported as a Research Assistant by the 21st Century COE program “Knowledge Information Infrastructure for Genome Science”.

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Authors and Affiliations

  1. Department of Pharmacy, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Keiko Hosohata, Satohiro Masuda, Atsushi Yonezawa, Toshiya Katsura & Ken-ichi Inui

  2. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Fumitaka Oike, Yasuhiro Ogura, Yasutsugu Takada, Hiroto Egawa & Shinji Uemoto

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  1. Keiko Hosohata
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  2. Satohiro Masuda
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Correspondence to Ken-ichi Inui.

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Hosohata, K., Masuda, S., Yonezawa, A. et al. MDR1 Haplotypes Conferring an Increased Expression of Intestinal CYP3A4 Rather than MDR1 in Female Living-Donor Liver Transplant Patients. Pharm Res 26, 1590–1595 (2009). https://doi.org/10.1007/s11095-009-9867-5

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