[Study on pulmonary delivery of peptide drugs in rats: effects of absorption enhancers on cellular membrane fluidity].
OBJECTIVE
To study the relationship between cellular membrane fluidity and relative bioavailability (Fr) of protein and peptide drugs combined with absorption enhancers after pulmonary administration in rats.


METHODS
A series of model drug salmon calcitonin (sCT) solutions with 6 absorption enhancers (Brij78, sodium cholate, sodium caprylate, 2-hydroxypropyl-beta-cyclodextrin, lecithin and chitosan) were prepared and then delivered to rats by pulmonary route. Serum drug concentration was determined by radioimmunoassay method. Using the techniques of electron spin resonance and fluorescence polarography, the effects of enhancers on pulmonary cellular membrane fluidity were investigated.


RESULTS
Fr values of sCT solution with some absorption enhancers (Brij78, sodium cholate, sodium caprylate, lecithin and chitosan) were significantly higher than those without enhancers. Brij78, lecithin and sodium caprylate, not only increased membrane lipid fluidity but also loosed the constitution of membrane protein. The effect of sodium cholate on membrane protein was low. Lipid fluidity was reduced and protein constitution was changed markedly, after pulmonary cellular membrane was treated by 0.5% chitosan solution. This result showed that the absorption enhancing of chitosan mainly came from its effects on membrane protein. Corresponded with lower Fr after pulmonary administration, 2-hydroxypropyl-beta-cyclodextrin (0.5% and 3%) had not significant effects on both lipid fluidity and protein constitution.


CONCLUSIONS
The effects of enhancers on pulmonary absorption of peptide drugs in vivo might be investigated on the grounds of determination of cellular membrane fluidity in vitro.
Wang
Zhi-Ying
ZY
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Zhang
Qiang
Q
D000042:Absorption; D000818:Animals; D001682:Biological Availability; D002116:Calcitonin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002210:Caprylates / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002686:Chitin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D048271:Chitosan; D004357:Drug Synergism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D008565:Membrane Proteins / Q000187:drug effects; D008968:Molecular Conformation; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020358:Sodium Cholate / Q000494:pharmacology
D002210:Caprylates; D008565:Membrane Proteins; D010713:Phosphatidylcholines; D002686:Chitin; C028815:salmon calcitonin; D002116:Calcitonin; D048271:Chitosan; D020358:Sodium Cholate; C031492:octanoic acid