Preclinical Animal Studies (2) - Routes And Volumes Of Administration

The pharmacokinetics of drugs vary significantly among different animal species, especially for oral administration. The table below highlights the gastrointestinal physiological differences across species, with pH being a major factor. For example, dogs exhibit a significant pH variation in gastric juice between fasting and fed states. Many compounds can ionize, and their solubility changes with pH. For instance, a sodium salt might have high solubility in a solvent but may dissociate into a free form with low solubility in the acidic environment of the stomach, leading to precipitation and reduced absorption. Human gastric pH is relatively low, and using simulated human gastric juice in precipitation experiments can mislead results when applied to animal studies. For instance, a sodium salt might precipitate at pH 1.2 but not at pH 4 or higher.

1. Routes of Administration

Different routes of administration require tailored formulation development strategies, such as selecting the appropriate dosage forms and solvent limits. In preclinical trials, small molecule administration methods include suspensions and solutions (both oil-based and water-based). Oral administration can utilize both forms, while intravenous (IV) injection typically requires solutions. Common routes of administration include:

1.Gastrointestinal Administration: This includes oral, sublingual, and rectal routes.

• Oral Administration: The most common, safe, convenient, and economical method, typically using tablets, capsules, and granules. In preclinical studies, solutions or suspensions are often used. However, some drugs have poor absorption due to their physicochemical properties, gastric mucosal irritation, or degradation by digestive enzymes and gastric acid, leading to reduced bioavailability and efficacy. Food can also affect drug absorption and should be considered in studies. For experimental animals, oral administration methods include direct oral (mixing drugs in water or feed for voluntary intake) and gavage (using a gavage needle to deliver the drug solution or suspension directly into the stomach). Direct oral administration is simple but less precise due to individual intake variations, making it less commonly used. Gavage is precise, allows dose control, and better simulates clinical oral administration, making it a widely accepted technique that researchers should master.
• Sublingual Administration: While the oral mucosa has a limited absorptive surface, it is significant for certain drugs, such as nitroglycerin, which is rapidly absorbed sublingually for quick therapeutic effects.
• Rectal Administration: Used when patients are vomiting or unconscious, rectal administration allows about 50% of the drug to bypass the liver, avoiding first-pass metabolism. It is also common in pediatric medication. However, rectal absorption is often irregular and incomplete, limiting its use.

2.Injectable Administration: This includes intravenous, intramuscular, and subcutaneous injections.

• Intravenous Injection: Directly injecting the drug into the bloodstream achieves rapid and accurate therapeutic levels, unmatched by other methods. However, the rapid introduction of high concentrations can increase adverse reaction risks, thus requiring careful solvent use.
• Intramuscular Injection: Water-soluble drugs are rapidly absorbed, suitable for oil-based solutions and certain irritants.
• Subcutaneous Injection: Suitable for non-irritant drugs, as it can cause severe pain and tissue necrosis if otherwise. Subcutaneous absorption is typically slow and consistent, providing prolonged effects.

3.Respiratory Administration: Inhalation of gases or volatile drugs allows absorption through the lung epithelium and respiratory mucosa, quickly entering the bloodstream due to the large surface area. Solutions can be nebulized for direct lung treatment. The main drawbacks are dosage control difficulties and complexity.

4.Transdermal Administration: Few drugs can rapidly penetrate intact skin, but absorption through the skin is generally proportional to the surface area covered and the drug's lipid solubility. The epidermis acts as a lipid barrier, but many solutes pass freely through the dermis. Damaged skin significantly increases absorption rates.

Overall, oral administration is the most economical and commonly used method. The principle is to prefer oral administration when feasible, intramuscular if necessary, and intravenous injections with caution, especially for traditional medicine injections. In preclinical studies, oral and intravenous routes are primary. The table below lists common administration routes and their abbreviations, with PO (oral) and IV (intravenous) being the most used.

2.Administration Volume

Differences in stomach capacity among test species limit the maximum oral dose volume. Excessive volumes can cause pain, excitement, physiological changes (such as electrolyte imbalances, increased blood pressure, and respiratory rates), and abnormal absorption. The table below provides volume guidelines for different species and administration routes. For oral administration, both mice and rats tolerate up to 10 mL/kg, while dogs and monkeys tolerate up to 5 mL/kg. Generally, larger animals have lower tolerance for administration volumes and excipients. Formulation development should balance concentration and volume. For example, if excipient content is high, reducing volume while maintaining dose might be necessary. Typically, doses are expressed in mg/kg, indicating the administered amount relative to body weight. For instance, a dose of 100 mg/kg in rats with a volume of 10 mL/kg requires a solution concentration of 10 mg/mL.