These findings provide new insight to the fact that the interindividual variability of methadone dosage requirement is polygenetic and cannot be explained by a single-gene effect.

Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp’s interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates.

The results of present study indicated that polygenic analysis may provide useful information in PHT therapy optimization.

No abstract

The drug‐injury relief system in Taiwan was implemented 20 years ago with the goal of providing timely relief for drug injuries incurred by the proper use of legal drugs. This system utilizes a nonlitigation expert review process to evaluate drug‐injury relief applications, and 2,732 applications have been reviewed from 1999−2016. Of these, 1,572 applications received relief payments, an approval rate of 58%. Average review timeframes per application have decreased from 248 days (2003–2011) to 182 days (2012–2016). Most adverse drug reactions (ADRs) for approved cases involved skin and subcutaneous tissue disorders (67%), with allopurinol being the primary culprit drug. A recent decline observed for such ADRs may reflect the influences of promotional activities and policy initiatives carried out according to informed analysis from drug‐injury relief applications, which suggests that the drug‐injury relief system can also play an important public health role in enhancing drug safety.