Document Detail

Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061.
MedLine Citation:
PMID:  19480558     Owner:  NLM     Status:  MEDLINE    
(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction. In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat. Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16-38% in rat and 54-61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25-50% bioavailability. The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26-38%. These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.
N J Attkins; A C Heatherington; J Phipps; H Verrier; I Huyghe
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Xenobiotica; the fate of foreign compounds in biological systems     Volume:  39     ISSN:  1366-5928     ISO Abbreviation:  Xenobiotica     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-18     Completed Date:  2009-10-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1306665     Medline TA:  Xenobiotica     Country:  England    
Other Details:
Languages:  eng     Pagination:  523-33     Citation Subset:  IM    
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK.
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MeSH Terms
Administration, Intranasal
Biological Availability
Caco-2 Cells
Dopamine Antagonists / pharmacokinetics*,  pharmacology
Dose-Response Relationship, Drug
Morpholines / pharmacokinetics*,  pharmacology
Phenols / pharmacokinetics*,  pharmacology
Rats, Sprague-Dawley
Receptors, Dopamine D3 / antagonists & inhibitors*,  metabolism
Sexual Dysfunction, Physiological / drug therapy
Reg. No./Substance:
0/(R)-3-(4-propylmorpholin-2-yl) phenol; 0/Dopamine Antagonists; 0/Morpholines; 0/Phenols; 0/Receptors, Dopamine D3

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