GENETIC CONTROL OF CICLOSPORIN ABSORPTION

Abstract

P1165 Aims: Ciclosporin is a narrow therapeutic index drug and has highly variable absorption. Intestinal cytochrome P450 and P glycoprotein both play important roles in the intestinal absorption of drugs and may be the cause of the between patient variability of ciclosporin. We investigated the frequency of the single nucleotide polymorphism C3435T in exon 26 of the MDR1 gene, to determine whether homozygotes have different C0 and C2 levels, as well as the dose of ciclosporin when compared to heterozygotes. We have also investigated whether CYP3A5 genotype influences ciclosporin absorption. The first objective of our study was to investigate whether there is a difference in dose requirements between different races when monitored on conventional through (C0) monitoring and two hours post dose (C2) monitoring. The second objective was to determine whether genetic polymorphism contributes to the between patients variability of ciclosporin. Methods: The MDR1 C345T polymorphism was investigated in 100 stable renal patients at least 6 months post transplant that attended outpatients clinic at Barts and The London. MDR-1 was genotyped using (PCR-FRLP) restriction length using Mbol enzyme. CYP3A5 was genotyped using Light Cycler real time PCR with specific probes and primer. Results: 21 patients were originally Asians from the Indian subcontinent, 75 patients originated from British Isles and Western Europe and 6 of our patients were from African continent. There were no significant differences in trough and two hour post dose concentrations or dose between C345T MDR1 homozygotes and heterozygotes. There were no differences between CYP3A5 genotypes. However, Asians had significantly higher (p<0.03) dose normalised C2 levels in comparison to Caucasians (mean concentration 363 versus 282μg/L/mg/kg). Asians also have significantly higher (p<0.01) normalised C0 levels in comparison to Caucasians (mean concentration 66 versus 48μg/L/mg/kg). Asians receive smaller mean dose of ciclosporin (0.4mg/kg vs. 0.5mg/kg, p<0.01). Conclusions: Asians required less ciclosporin in order to achieve same concentration in the blood. However we did not find that the difference was related to the genotypes we investigated. Other pharmacogenomic investigations are being carried out to determine the source of this difference.