title: Solute disposition in the rat lung in vivo and in vitro: determining regional absorption kinetics in the presence of mucociliary escalator.
abstract: Solute absorption from the airways was compared and modeled in vivo and in vitro isolated perfused rat lung (IPRL), and its regional kinetic descriptors in the presence of competing mucociliary escalator were estimated. 7.4 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA), FITC-labeled dextran 40 (FD-4) and sodium fluorescein (F-Na) were used as model solutes. They were reproducibly administered into the airways in a range of doses in vivo and in vitro IPRL, and their initial deposition and subsequent absorption profiles compared. Each of the absorption data was fitted across doses to a kinetic model in which rate constants for Michaelis-Menten-type active (V(max,P) and K(m,P)) and/or first-order passive (k(a,P)) absorption and mucociliary escalator (k(E)) were estimated simultaneously. Statistically indistinguishable initial solute distribution was ensured in vivo and in vitro. The absorption profiles for F-PHEA were kinetically identical in vivo and in vitro, and their modeling analysis revealed the presence of competing, solute-independent pulmonary-to-bronchial mucociliary escalator with a half-life of 28.9 min. F-PHEA's active absorption was found to be 77 times faster than its passive absorption, yet this was present only in the pulmonary region. Passive solute absorption was inversely related to solute molecular weight [F-PHEA < FD-4 < F-Na]. Bronchial absorption was shown for F-Na in vivo and its rate indistinguishable from that from the pulmonary region. Thus, a single kinetic model was developed, enabling regional absorption kinetic analysis both in vivo and in vitro, in the presence of competing, solute-independent mucociliary escalator.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, P.O. Box 980533, Richmond, Virginia 23298, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakagami
authors.forename: Peter R
authors.initials: PR
authors.lastname: Byron
authors.forename: Jurgen
authors.initials: J
authors.lastname: Venitz
authors.forename: Frantisek
authors.initials: F
authors.lastname: Rypacek
mesh_terms: D000042:Absorption / Q000502:physiology; D000818:Animals; D003287:Contrast Media / Q000493:pharmacokinetics; D003911:Dextrans / Q000493:pharmacokinetics; D019793:Fluorescein / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D007442:Intubation, Intratracheal / Q000379:methods; D008168:Lung / Q000378:metabolism*; D008297:Male; D009079:Mucociliary Clearance / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions
chemical_list: D003287:Contrast Media; D003911:Dextrans; D012996:Solutions; C015219:fluorescein isothiocyanate dextran; D016650:Fluorescein-5-isothiocyanate; D019793:Fluorescein