In vivo screening of oral formulations using rats: Effects of ingested water volume on oral absorption of BCS class I and III drugs from immediate-release formulations

This study investigated the effects of ingested water volume on drug absorption to confirm the applicability of rats for oral formulation screening and to optimize the experimental conditions. Mini-sized capsules (ϕ2.6 × 7.2 mm) or tablets (ϕ2.5 × 2.2 mm) as immediate-release formulations containing acetaminophen (ACE), metoprolol tartrate (MET), and atenolol (ATE) were administered to the fasted rats with 0.5 or 1 mL of water with pre-dissolved deuterium-labeled ACE (ACE-d4). Mean absorption times (MATs) of ACE, ATE, and MET from capsule form when ingested with 0.5 mL of water were significantly longer than those with 1 mL of water. Similar effects were detected for ACE and MET from tablet form. The ingested water volume significantly influenced the mean dissolution time of ACE from capsule form calculated from MATs of ACE and ACE-d4. One milliliter of ingested water rather than 0.5 mL revealed that absorption rate constants of drugs strongly depended on the membrane permeability of drugs. Furthermore, the rate-limiting step of oral absorption of all drugs administered with 1 mL of water corresponded well with that in humans, irrespective of formulations. This study demonstrated that 1 mL of water can sufficiently dissolve and empty the drugs from the stomach, suggesting that rats can be used to evaluate oral drug absorption from immediate-release formulations. [Display omitted]