Influence of cytochrome P450 and ABCB1 genetic polymorphisms on drug efficacy in narcolepsy with cataplexy

Abstract

Treatments for narcolepsy-cataplexy (NC) are so far only symptomatic and aim to reconsolidate sleep and waking states as well as cataplexy attacks. The patients’ clinical response is influenced by a high interindividual variability. This leads, in clinical practice, to an empirical case-by- case management, mainly based on increasing drug dosages, but without a precise clue of the mechanisms of such variability. Genetic polymorphisms of cytochrome P450 (CYP450) are involved in drug metabolism and known to be responsible for the interindividual variability of drug response in different population groups. We genotyped CYP450 genes, CYP3A4 and CYP3A5, involved in the metabolism of two common NC drugs (i.e. modafinil (Mod), a wake promoting agent, and venlafaxine (Ven), a noradrenaline- serotonine reuptake inhibitor). Moreover, we genotyped the glycoprotein-P ABCB1(P-gp), also called multidrug resistance protein 1, a transmembrane efflux pump. Finally, genotypes were correlated with Mod and Ven efficacy and dosage, to provide a clue for the interindividual variability in clinical response of NC patients. 45 Caucasian NC patients (28 males, mean age 42 ± 20 y.o.), on chronic therapy with Mod alone or Mod plus Ven underwent blood withdrawal for genetic analysis. Mod and Ven efficacy was empirically scored by a sleep expert (1 = full, 2 = mild, 3 = low efficacy). Multiplex PCR was used for CYP3A4, CYP3A5 and P-gp loci amplification, followed by enzymatic purification, minisequencing reaction, and capillary electrophoresis typing. Out of 45 patients 17 were on Mod alone (38%), 28 on Mod plus Ven (62%). No significant correlation was found between CYP3A4/CYP3A5 genotypes and Mod or Ven efficacy or dosage. The CGC/TTT P- gp-haplotype (wild type/mutated allele), corresponding to a decreased activity, showed a significant correlation with an increased Mod efficacy ( p = 0.017). CGC/TTT haplotype was also the most represented in NC, according to general Caucasian population frequency distribution. This is the first attempt to correlate the interindividual variability of drug response to Mod and Ven in NC patients with the genotypes of proteins involved in their metabolism and transport. An increased Mod efficacy resulted to be related to a partially decreased activity of P-gp (partially mutated haplotype), suggesting that the Mod efficacy may be related to the intracellular permanence of Mod, consequent to damaged cell efflux. We thank the patients of the Italian Narcolepsy Association (AIN) for the precious collaboration.