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Titolo:
Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers
Autore:
Addison, RS; Parker-Scott, SL; Eadie, MJ; Hooper, WD; Dickinson, RG;
Indirizzi:
Univ Queensland, Royal Brisbane Hosp, Ctr Studies Drug Disposit, Brisbane,Qld 4029, Australia Univ Queensland Brisbane Qld Australia 4029 Brisbane,Qld 4029, Australia
Titolo Testata:
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 9-10, volume: 56, anno: 2000,
pagine: 715 - 721
SICI:
0031-6970(200012)56:9-10<715:SDOVAD>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMA-PROTEIN BINDING; PHARMACOKINETIC INTERACTION; ACID; GLUCURONIDATION; METABOLITES; KINETICS; HUMANS; CARBAMAZEPINE; FELBAMATE; EXCRETION;
Keywords:
valproate; diflunisal; glucuronidation;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Addison, RS Univ Queensland, Royal Brisbane Hosp, Ctr Studies Drug Disposit, Clin Sci Bldg, Brisbane, Qld 4029, Australia Univ Queensland Clin Sci Bldg Brisbane Qld Australia 4029 alia
Citazione:
R.S. Addison et al., "Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers", EUR J CL PH, 56(9-10), 2000, pp. 715-721

Abstract

Objective: The effects of coadministration of the non-steroidal anti-inflammatory drug diflunisal (DF) on glucuronidation and P-oxidation of the antiepileptic agent valproic acid (VPA), and of VPA on DF glucuronidation, werestudied in human volunteers. Methods: Seven healthy male volunteers received sodium valproate (NaVPA, 200 mg) orally twice daily for 7 days, after which all drug intake ceased for 1 month. The volunteers then took DF (250 mg) orally twice daily for 7 days. Both drugs were then taken (at the same doses as previously) twice daily for 7 days. On day 7 of each dosing phase, serial blood samples and all urine passed over the 12-h inter-dosing interval were collected. VPA, DF andselected metabolites were analysed using validated methods. Statistical comparisons of pharmacokinetic parameters were made using paired Student's t-tests. Results: Mean plasma concentrations of total VPA were lower and apparent plasma clearances significantly higher during DF coadministration. This was associated with a significant 20% increase in the unbound fraction of VPA (from 6.6 +/- 1.3% to 7.9 +/- 1.8%). The apparent clearance of unbound VPA was not different. There was no evidence of any significant effect of DF coadministration on VPA metabolism: urinary recoveries of and formation clearances to urinary VPA-glucuronide, E-2en-VPA, 3-oxo-VPA and 4-en-VPA were notsignificantly altered. However, there was a highly significant 35% increase in the area under the plasma concentration-time curve from 0-12 h (AUC(0-12)h) Of 3-oxo-VPA and its renal clearance was lower, though not significantly so. VPA coadministration had no effect on DF pharmacokinetics or formation clearances of DF to its acyl glucuronide (DAG), phenolic glucuronide (DPG) or sulfate (DS) conjugates. However, plasma AUC(0-12h) values of the glucuronides were significantly lower and their renal clearances higher (though significantly so only in the case of DPG) during VPA coadministration. Conclusions: Steady-state coadministration of VPA and DF leads to a significant displacement of VPA from plasma protein binding sites. There was no evidence of competition for glucuronidation capacity or other metabolic interactions. Rather, the interactions detected appeared to be renal in nature,with renal clearance of 3-oxo-VPA being reduced by DF coadministration, and renal clearance of DPG and perhaps DAG being increased by VPA coadministration.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 19:21:59