MDR1 polymorphisms effect cyclosporine AUC0-4 values in Behçet’s disease patients

Yoshihiko Katsuyama¹, Masao Ota², Nobuhisa Mizuki³, Akiko Ito³, Eiichi Okada⁴, Shigeaki Ohno⁵, Tamihide Matsunaga¹, Hirofumi Fukushima², Shigeru Ohmori¹

¹Department of Pharmacy, Shinshu University Hospital, Japan; ²Department of Legal Medicine, Shinshu University School of Medicine, Japan; ³Department of Ophthalmology, Yokohama City University School of Medicine, Japan; ⁴Okada Eye Clinic, Japan; ⁵Department of Ophthalmology, Hokkaido University School of Medicine, Japan

Abstract: Cyclosporine (CYA) is used to preventing ocular attacks in Behçet’s disease patients. Yet there are inter-individual variations in efficacy. In order to analyze the relationship between CYA fluctuation with treatment effectiveness and genetic factors, an association of area under the plasma concentration time at 0–4 hours (AUC0-4) values and polymorphism for multidrug resistance 1 (MDR1) and cytochrome3A5 (CYP3A5) genes was investigated. Genomic DNA was collected from 17 Japanese patients with Behçet’s disease. MDR1 polymorphisms were determined by direct sequencing from amplified products for promoter and two exons regions and CYP3A5 polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. AUC0-4 value was determined by the trapezoidal rule from the data of 5 times blood sampling at 0–4 hours. The haplotype 2 in the promoter region of MDR1 influenced significantly lower AUC0-4 values, implying absorption decline of CYA. The CYP3A5 polymorphisms had no direct influence on the effectiveness for CYA treatment. In the relation of CYA and AUC0-4 in the patients, 7 cases were grouped effective and 4 ineffective. Though there was no difference in dosage, the trough values for AUC0-4 were higher in the effective group compared to the ineffective group.

Keywords: cyclosporine, MDR1 gene, Behçet’s disease, AUC0-4value