Monica Rodriguez(1), Nerea Leal(1), Rosario Calvo(1), Elena Suarez(1), Ignacio Ortega(1), John C Lukas(2)
(1)Department of Pharmacology, School of Medicine, University of the Basque Country, Leioa, Vizcaya, Spain; (2)Department of Pharmacy, Laboratory of Pharmacokinetics and Biopharmaceutics, University of Athens, Greece
Background: The pharmacokinetics (PK) and pharmacodynamics (PD) of methadone (M), an opiate agonist, shows still unclarified inter-individual variability [1]. M is highly bound to a1-acid glycoprotein (AGP). AGP is known to increase in several pathological situations (e.g. infection, inflammation), and may affect the PK/PD of several drugs dependent on and also independently of protein binding [2].
Purpose: To characterise the influence of high levels of AGP on methadone’s analgesic effect and PK in the animal model.
Methods: AGP levels were increased by two different methods: (a) experimental inflammation with turpentine oil (inflammation is known to alter per se the PK of several drugs) [3] and (b) by directly infusing the protein. Tail-flick analgesia was measured after i.v. M injection (0.35 mg/kg), from 0 to 120 min, in control (n=20), turpentine pretreated (TP) (n=10), and AGP infused (AI) (n=16) male Sprague-Dawley rats. The PK were evaluated in separate control (n=20; m=23), TP (n=30; m=37) and AI (n=14; m=16) rats, after the same dose of M i.v.. The unbound fraction (fu) as well as AGP and albumin levels were measured. A bicompartmental model best described the PK using NONMEM. The objective function, SE estimates and residual plots were used for comparisons.
Results: The area under the effect-time curve was (mean ± SD) 978 ± 130 min in the AI group, 1789 ± 295 min in the TP group, both significantly lower than the 4871 ± 393 min in the control (p<0.0001). On the contrary, the concentration (Cp) vs time profiles were higher in TP and particularly AI (C0=1141.2 m g/L and 208.3 m g/L in AI and TP rats respectively vs 123.2 m g/L in controls) and therefore corresponded inversely to the effect vs time relative magnitudes. The FOCE PK parameters were, for the control central clearance (mean [interindividual CV%]) CL=0.024 L/min (19%), central volume Vc=0.68 L (31%), intercompartmental clearance Q=0.11 L/min (31%) and deep tissue volume Vt=0.93 L (31%). For TP, CL=0.016 L/min (19%), Vc=0.39 L (21%), Q=0.04 L/min (79%), Vt=0.58 L (31%). For AI, CL=0.006 L/min (50%), Vc=0.06 L (31%), Q=0.01 L/min (31%), Vt=0.07 L (no CV estimate). All differences were significant compared to the controls (p<0.005). Covariate modelling was hindered by the destructive sampling design [4]. For TP, Vc=0.69 – 0.23*AGP + 0.16*(AGP-1.7)2 (5%). The AGP levels were 0.4 g/L, 1.6 g/L and 6 g/L for control, TP and the AI, and the fu was 23%, 11% and 9% respectively. The PK parameters were not corrected by the fu.
Conclusions: Increased AGP levels relate to significant changes in the PK parameters and their population statistics. AGP appears responsible for these alterations, beyond protein binding (i.e. lack of correction by the fu). We are currently evaluating PD models to explain the lack of relationship between Cp and effect. The results could relate to man under conditions of infection, frequent in methadone treated patients.
References:
[1] Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: Implication for the treatment of opioid dependence. Clin Pharmacokinet 2002; 41:1153-93
[2] Fournier T, Medjoubi-N N, Porquet D: Alpha-1 acid glycoprotein. Biochimica et Biophysica Acta 2000; 1482: 157-71
[3] Jauregizar N, Calvo R, Suarez E, Quintana A, Raczka E, Lukas JC: Altered disposition and effect of lerisetron in rats with elevated alpha1-acid glycoprotein levels. Pharm Res 2001; 18:838-45
[4] Ette EI, Kelman AW, Howie CA, Whiting B: Analysis of animal pharmacokinetic data: performance of the one point per animal design. J Pharmacokin Biopharm 1995; 23:551-66
Reference: PAGE 12 (2003) Abstr 419 [www.page-meeting.org/?abstract=419]
Poster: poster