Generation of High-Quality Pharmacokinetic Data from Parallel Tail Vein Dosing and Bleeding in Non-cannulated Rats.

Abstract

It is common practice to use cannulated rats for\xa0pharmacokinetic (PK)\xa0in-life studies as it yields high quality PK parameter estimation. While offering many benefits, cannulation requires surgery, post-surgical care, and cannula maintenance. As an alternative approach, the strategy of dosing and bleeding rats via the tail vein in a single experiment is technically feasible and theoretically offers many benefits. Unfortunately, however, as reported by F\xa0Tse\xa0et. al in 1984 (J Pharm Sci 73: https://doi.org/10.1002/jps.2600731128), parallel tail dosing and bleeding is scientifically flawed and yields inaccurate estimation of PK parameters following intravenous administration. The underlying causality of poor data quality has not been addressed in over 35 years. To overcome the technical flaws associated with parallel tail dosing and bleeding, we have developed a Tail-Dose-Bleed (TDB) method as a substitute for use of cannulated rats. Specifically, the method introduces a flush procedure after dosing,\xa0uses separate tail veins for dosing and bleeding, and\xa0adjusts dosing and sampling to the proximal and distal portions of the tail, respectively. To demonstrate the proof of principle for this TDB technique, several cassette dosing studies\xa0were conducted.\xa0The performance of the TDB technique is compared\xa0in\xa0both stand alone and animal crossover studies employing conventional jugular/femoral bleeding and dosing. The poor data via tail dosing and bleeding previously described by Tse et al. are also recapitulated using their described approach. To ensure broad applicability of the TDB technique, data were generated utilizing compounds\xa0of diverse\xa0physical chemical properties manifesting a\xa0range of clearance and/or volume of distribution characteristics.\xa0These data\xa0demonstrate that the TDB approach yields comparable PK profiles and parameters\xa0as compared to conventional femoral dosing / jugular bleeding.\xa0Using this newly described TDB\xa0procedure, we demonstrate the ability to overcome documented data quality\xa0issues when dosing and bleeding via the tail. The TDB technique has numerous operational advantages of reduced study turnaround time and improved cost effectiveness, but most importantly, addresses key animal welfare concerns relevant to institutional animal care and use committees (IACUC). The notable advantage here is reduced animal stress and discomfort by eliminating the need for surgery and recovery. And by consequence, allows for animals to be group housed and re-used without concern for loss of cannula patency. The tail dose and bleed method\xa0is\xa0simple and appears readily transferable to other laboratories.