Functional Impact of ABCB1 Variants on Interactions Between P-Glycoprotein and Methadone.
Functional Impact of ABCB1 Variants on Interactions between P-Glycoprotein and Methadone.
PLoS One. 2013; 8(3): e59419
Hung CC, Chiou MH, Teng YN, Hsieh YW, Huang CL, Lane HY
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.
HubMed – Methadone
Effects of prototypic calcium channel blockers in methadone-maintained humans responding under a naloxone discrimination procedure.
Eur J Pharmacol. 2013 Mar 21;
Oliveto A, Mancino M, Sanders N, Cargile C, Benjamin Guise J, Bickel W, Brooks Gentry W
Accumulating evidence suggests that L-type calcium channel blockers (CCBs) attenuate the expression of opioid withdrawal and the dihydropyridine L-type CCB isradipine has been shown to block the behavioral effects of naloxone in opioid-maintained humans. This study determined whether two prototypic L-type CCBs with differing chemical structures, the benzothiazepine diltiazem and the phenylalkamine verapamil, attenuate the behavioral effects of naloxone in methadone-maintained humans trained to distinguish between low-dose naloxone (0.15mg/70kg, i.m.) and placebo under an instructed novel-response drug discrimination procedure. Once discrimination was acquired, diltiazem (0, 30, 60, 120mg) and verapamil (0, 30, 60, 120mg), alone and combined with the training dose of naloxone, were tested. Diltiazem alone produced 33-50% naloxone- and novel-appropriate responding at 30 and 60mg and essentially placebo-appropriate responding at 120mg. Verapamil alone produced 20-40% naloxone- and 0% novel-appropriate responding. Diltiazem at 60mg decreased several ratings associated with positive mood and increased VAS ratings of “Bad Drug Effects” relative to placebo, whereas verapamil increased ratings associated with euphoria. When administered with naloxone, diltiazem produced 94-100% naloxone-appropriate-responding with 6% novel-appropriate responding at 60mg (n=3). When administered with naloxone, verapamil produced 60-80% naloxone- and 0% novel-appropriate responding (n=5). Diltiazem decreased diastolic blood pressure and heart rate whereas verapamil decreased ratings of arousal relative to placebo. These results suggest that CCBs with different chemical structures can be differentiated behaviorally, and that diltiazem and verapamil do not attenuate the discriminative stimulus effects of naloxone in humans at the doses tested.
HubMed – Methadone
Reduction in arterial stiffness and vascular age by naltrexone-induced interruption of opiate agonism: a cohort study.
BMJ Open. 2013; 3(3):
Reece AS, Hulse GK
To prospectively assess if opiate antagonist treatment or the opiate-free status could reverse opiate-related vasculopathy.Longitudinal Open Observational, Serial ‘N of One’, over 6.5 years under various treatment conditions: opiate dependence, naltrexone and opiate-free.Primary care, Australia.20 opiate-dependent patients (16 males: 16 cases of buprenorphine 4.11±1.17 mg, two of methadone 57.5±12.5 mg and two of heroin 0.75±0.25 g).Studies of central arterial stiffness and vascular reference age (RA) were performed longitudinally by SphygmoCor Pulse Wave Analysis (AtCor, Sydney). PRIMARY OUTCOMES: Primary outcome was vascular age and arterial stiffness accrual under different treatment conditions.The mean chronological age (CA) was 33.62±2.03 years. The opiate-free condition was associated with a lower apparent vascular age both in itself (males: p=0.0402 and females: p=0.0360) and in interaction with time (males: p=0.0001 and females: p=0.0004), and confirmed with other measures of arterial stiffness. The mean modelled RA was 38.82, 37.73 and 35.05 years in the opiate, naltrexone and opiate-free conditions, respectively. The opiate-free condition was superior to opiate agonism after full multivariate adjustment (p=0.0131), with modelled RA/CA of 1.0173, 0.9563 and 0.8985 (reductions of 6.1% and 11.9%, respectively).Data demonstrate that opiate-free status improves vascular age and arterial stiffness in previous chronic opiate users. The role of opiate antagonist treatment in achieving these outcomes requires future clarification and offers hope of novel therapeutic remediation.
HubMed – Methadone
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