Alpha-1-acid glycoprotein directly affects the pharmacokinetics and the analgesic effect of methadone in the rat beyond protein binding
✍ Scribed by Monica Rodriguez; Ignacio Ortega; Itziar Soengas; Nerea Leal; Elena Suarez; Rosario Calvo; John C. Lukas
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 172 KB
- Volume
- 93
- Category
- Article
- ISSN
- 0022-3549
No coin nor oath required. For personal study only.
✦ Synopsis
Methadone is a basic drug highly bound to a1-acid glycoprotein (AGP), a plasma protein that increases in several pathological situations. Our aims were to evaluate the processes (pharmacokinetics-PK and/or pharmacodynamics-PD) associated with changes of methadone analgesia under conditions of increased AGP, and whether these changes are dependent on binding, secondary to a pathology, or directly attributable to AGP. AGP levels, in rats, were increased by two different methods: (a) experimental inflammation with turpentine oil (TP), and (b) by directly infusing the protein (exo-AGP). Both had a corresponding control group. Tail-flick analgesia and PK were evaluated after methadone dose (0.35 mg/kg i.v.). Bicompartmental PK parameters as well as interanimal and assay variabilities were estimated using NONMEM. The relationship between Cp and analgesic effect (PD) was analyzed with WINNONLIN. AGP levels in both pretreated groups (TP and exo-AGP) were significantly increased, and the unbound fraction (fu) was decreased, compared to controls. All PK parameters were lower in the pretreated groups, but in exo-AGP the difference was maintained even when corrected by fu. Paradoxically, also in exo-AGP the analgesic effect was practically nonexistent, although the unbound Cp remained high, possibly associated to a change in the PD. AGP appears responsible for alterations in both PK and PD, beyond protein binding and inflammatory processes.