ABSTRACT
The main purpose of this study was to estimate the net percutaneous absorption of physiologically active peptides in vitro. The degradation of two peptides, Leu-enkephalin (Enk) and Tyr-Pro-Leu-Gly amide (TPLG), during skin penetration and on the dermal side following penetration, and the prevention of degradation by some protease inhibitors, were investigated using rat skin in vitro. In addition, these permeation and degradation data were analyzed using a kinetic model. These peptides were rapidly degraded in the receptor fluid of a Franz diffusion cell (rate constant: 0.977 h(-1) for Enk and 0.250 h(-1) for TPLG). The addition of phenylmethylsulfonyl fluoride (PMSF) and phenanthroline and the pretreatment of skin with these inhibitors prevented almost completely any degradation in the receptor fluid and skin, respectively. The pretreatment of skin with PMSF and phenanthroline had no effect on the penetration of dextran (1000 Da). The degradation rate constant during skin penetration, calculated from the difference in the penetration rate constants via pretreated and untreated skins, was also high (0.037 h(-1) for Enk and 0.050 h(-1) for TPLG). A kinetic model including an input rate (zero-order), the permeation rate across the viable skin (first-order) and the degradation rate in skin (first-order) was sufficient to describe the apparent steady-state flux of the peptides through skin. We have, thus, established a method for measuring the true flux of peptides across skin in vitro and a kinetic model which simply describes the skin penetration of peptides.
Subject(s)
MSH Release-Inhibiting Hormone/analogs & derivatives , Peptides/pharmacokinetics , Skin Absorption/physiology , Administration, Cutaneous , Algorithms , Animals , Biotransformation , Dextrans/metabolism , Enkephalin, Leucine/administration & dosage , Enkephalin, Leucine/pharmacokinetics , MSH Release-Inhibiting Hormone/administration & dosage , MSH Release-Inhibiting Hormone/pharmacokinetics , Male , Models, Biological , Phenanthrolines/pharmacology , Protease Inhibitors/pharmacology , Rats , Skin Absorption/drug effectsABSTRACT
The entire country has become more concerned with healthcare costs due to managed care, capitation risk-based contracts, and the near elimination of the cost-plus reimbursement system. Clinical pathways have become one way to reduce unnecessary resource consumption by reducing provider variance, improving clinical outcomes, and reducing cost. We present here our rationale and process for developing a common clinical pathway for normal vaginal delivery in a large and varied multihospital system. We also discuss how this new pathway is expected to improve quality of care and reduce costs.
