Alpha‐1‐acid glycoprotein directly affects the pharmacokinetics and the analgesic effect of methadone in the rat beyond protein binding

Modeling Methadone Pharmacokinetics in Rats in Presence of P-glycoprotein Inhibitor Valspodar

“…In absence of valspodar, a biphasic decline in plasma levels was observed after i.v. administration of methadone, and the pharmacokinetic parameters obtained were similar to those previously reported for other authors (22,26). The simultaneous analysis of both administration routes, allowed us to estimate the absolute oral bioavailability, besides the others pharmacokinetic parameters, and to evaluate valspodar_s effect on its variability.…”

“…Based on previous population pharmacokinetic analysis of methadone in rats (22,26), an open two-compartment pharmacokinetic model with linear elimination from the central compartment was used to describe the disposition of methadone in rats. The absorption after p.o.…”

The Role of Unbound Drug in Pharmacokinetics/Pharmacodynamics and in Therapy

“…Finally, the capacity of AGP of directly modulating the PK and PD has been demonstrated in another PK/PD study with methadone in two groups of animals where the levels of AGP were increased via experimental inflammation and by exogenous administration of AGP [47]. It was observed that although the unbound fraction was reduced in both groups, all PK parameters, total and unbound, were also reduced in the pretreated groups, which lead to greater total and unbound plasma concentrations of drug.…”

“…For example, in an experimental study in the rat with methadone, different volumes of distribution were observed between male and female without changes in the fu [46]. Nevertheless, in another study where there was an increase in binding, due to exogenous administration of plasma proteins, the reduction in V was not parallel to the reduction in the fu and a global PK study was able to prove that there was an intrinsic change in Vu, possibly caused by the proper protein [47].…”

“…Indeed, integrated PK/PD models, relating the dose with the response via combined PK and PD models permitted, for example, to show that AGP may alter the pharmacological response independently of modifications in binding [47]. Importantly also, the unbound form of the potency reflects the actual receptor affinity, so it can be estimated from in vitro receptor binding studies and should have fair species independence.…”