CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients
1
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
2
Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
3
Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan
4
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
5
Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-6, Shinkawa, Mitaka-city, Tokyo 181-8611, Japan
6
Department of Pharmacy, International University of Health and Welfare Narita Hospital, 852 Hatakeda, Narita 286-0124, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4347; https://doi.org/10.3390/ijms21124347
Received: 4 May 2020
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Revised: 12 June 2020
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Accepted: 16 June 2020
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Published: 18 June 2020
(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)
Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.
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Keywords:
mucosal concentration; clinical activity index; multidrug resistance 1; polymorphism; inflammatory bowel disease
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MDPI and ACS Style
Yamamoto, Y.; Nakase, H.; Matsuura, M.; Maruyama, S.; Masuda, S. CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients. Int. J. Mol. Sci. 2020, 21, 4347. https://doi.org/10.3390/ijms21124347
AMA Style
Yamamoto Y, Nakase H, Matsuura M, Maruyama S, Masuda S. CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients. International Journal of Molecular Sciences. 2020; 21(12):4347. https://doi.org/10.3390/ijms21124347
Chicago/Turabian StyleYamamoto, Yuki, Hiroshi Nakase, Minoru Matsuura, Shihoko Maruyama, and Satohiro Masuda. 2020. "CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients" International Journal of Molecular Sciences 21, no. 12: 4347. https://doi.org/10.3390/ijms21124347
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