Laboratory Animals in Pharmacology

Laboratory Animals in Pharmacology

1. Definition, rationale & principles of animal use in pharmacology

• Experimental pharmacology studies drug action at the level of the whole animal, isolated organ, or tissue; the laboratory animal is the substrate on which pharmacodynamic, pharmacokinetic, and toxicological hypotheses are tested before human exposure (Medhi Ch.1, pp.3–6).
• Drug development is a three-stage process: Stage I hit-and-lead identification (target ID → cloning → combinatorial chemistry → high-throughput screening, HTS/UHTS); Stage II preclinical studies done in vitro and in vivo in animals (pharmacodynamics, pharmacokinetics, acute/chronic/genotoxicity) to derive the maximum recommended starting dose (MRSD); Stage III clinical trials (Phase 0–IV) using the MRSD-derived safe starting dose (SSD) with a safety factor (Medhi Ch.1, pp.5–6).
• Why animals are used — the understanding of drug action at organ/tissue level rests on >200 years of animal work; an animal model tests possibilities "difficult or impossible" to test in the target species, valid when two species "strongly resemble each other in particular ways" (Medhi Ch.1, pp.39–40).
• Three governing objectives of animal-model selection (Medhi Ch.1, p.6):
  • Use an animal phylogenetically closer to man, OR
  • Use an animal in which the process under investigation is as close as possible to that in man, OR
  • An animal whose anatomy, physiology and biochemistry are considered similar for the specific system studied.
• Two overarching principles of pharmacological products — (1) all therapies must meet the same standards of preclinical + clinical evidence of efficacy and safety; (2) substances used as drugs can be toxic under certain conditions (Medhi Ch.1, p.4).
• Historical anchors that shaped animal pharmacology: François Magendie and Claude Bernard developed experimental animal physiology/pharmacology (Bernard = "father of physiology and prince of vivisectors"); Antoine Lavoisier used a guinea pig to prove respiration is combustion; Stephen Hales measured blood pressure in the horse; Louis Pasteur demonstrated the germ theory by giving anthrax to sheep (1880s) (Medhi Ch.1, pp.3–4).