Pharmacokinetics of pseudoephedrine in rats, dogs, monkeys and its pharmacokinetic-pharmacodynamic relationship in a feline model of nasal congestion.
Drug Metab Lett
; 4(2): 56-61, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-20446910
ABSTRACT
The objectives of these studies were to characterize the pharmacokinetics (PK) of the nasal decongestant pseudoephedrine (PSE) in rats, dogs, and monkeys, and to evaluate its lower gastrointestinal tract regional bioavailability in rats. An LC-MS/MS assay with a lower limit of quantification (LLOQ) of 0.4 ng/mL of plasma was developed for the analysis of PSE in animal plasma. The total body clearance (CL) was the highest in rats (78 mL/min/kg), lowest in monkeys (15 mL/min/kg) and the dog averaged in between (33 mL/min/kg). The volume of distribution at steady state (Vdss) ranged from 3-5 L/kg in all species. In rats and dogs, the mean half-lives (t1/2) was ≈1.5 hr, while in monkeys the mean t1/2 was 4.6 hr, comparable to that observed in adult humans (4-8 hr). The oral bioavailability was 38, 58 and 78% in rats, dogs and monkeys. The bioavailability following intra-ileum or intra-colonic administration in rats was superior to that following oral dosing (66% and 78%, respectively) suggesting that colonic absorption may be compensating for the short half-life, thus enabling successful QD sustained release formulations of PSE. The pharmacokinetic/pharmacodynamic relationship (PK/PD) of PSE was also investigated in a feline model of nasal congestion to establish efficacious trough concentrations in cats for a comparison with that in humans. The PK/PD in the cat model followed a sigmoid Emax model with an EC50 (plasma concentration that elicits 50% of the maximum response) of 0.32 ±0.05 (SD) µM consistent with human plasma concentrations required for efficacy.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Descongestionantes Nasais
/
Obstrução Nasal
/
Pseudoefedrina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Drug Metab Lett
Assunto da revista:
FARMACOLOGIA
/
METABOLISMO
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos