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Slow Gastric Tube Infusion as an Approach for Assessment of Controlled Release in Rodents
Author(s) -
Small Kersten,
Lieber Gissela,
Bateman Thomas,
Ormes James,
Shen Xialoan,
Madwed Jeffrey
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1027.2
Subject(s) - cmax , bolus (digestion) , stomach , medicine , bioavailability , pharmacodynamics , pharmacokinetics , infusion pump , pharmacology , blood pressure , continuous infusion , anesthesia , heart rate
Methods in rodents to inform on oral controlled release (CR) formulations in the drug discovery process are limited. To address this problem, here we describe slow gastric infusion in rats as an approach that may allow for more informed decision‐making regarding investment in formulation based CR. To evaluate this approach, we used a novel orally bioavailable NO donor to determine whether slow compound delivery directly to the stomach would extend the duration of action of blood pressure (BP) lowering for a compound with a short T1/2 and minimize abrupt decreases in BP and increases in heart rate (HR) observed for vasorelaxants with early Tmax and high Cmax. BP and HR are particularly advantageous pharmacodynamics (PD) readouts because continuous measurements provide rich data sets for PK/PD comparisons. To inform on study design, an aqueous vehicle for compound solubilization was identified (30% HPBCD) and used to determine dose and predict plasma level concentrations following slow gastric infusion. For PD studies, Sprague‐Dawley rats were instrumented with telemetry and gastric tubes. After surgical recovery, rats were treated with L‐NAME to induce hypertension followed by a 30 mg/kg dose of NO donor compound, administered as a bolus and a slow 24‐hr infusion via gastric tube. Compared to a bolus dose, slow gastric infusion extended the duration of BP lowering, minimized the abrupt fall in blood pressure, and inhibited the increase in heart rate. In conclusion, our data support slow gastric infusion as a means to test PK/PD hypotheses which may inform on effectiveness of CR formulations.