The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients.

Abstract

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

• Authors: Maizumi Furuse, Shuhei Hosomi, Yu Nishida, Shigehiro Itani, Yuji Nadatani, Shusei Fukunaga, Koji Otani, Fumio Tanaka, Yasuaki Nagami, Koichi Taira, Noriko Kamata, Toshio Watanabe, Kenji Watanabe, Yasuhiro Fujiwara
• Journal: PloS one (PLoS One) Vol. 16 Issue 4 Pg. e0250597 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 33886687 (Publication Type: Journal Article)

Chemical References

• ABCC2 protein, human
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• CYP3A5 protein, human
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Tacrolimus

Topics

• Adult
• Colitis, Ulcerative (drug therapy, genetics, pathology)
• Cytochrome P-450 CYP2C19 (genetics)
• Cytochrome P-450 CYP3A (genetics)
• Drug-Related Side Effects and Adverse Reactions (genetics, pathology)
• Female
• Genotype
• Humans
• Inactivation, Metabolic (genetics)
• Male
• Middle Aged
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Tacrolimus (administration & dosage, adverse effects, pharmacokinetics)