From In Vitro to In Vivo: Optimization of ADME and Toxicology Properties

A successful drug candidate must have favorable pharmacokinetics in addition to potent and selective binding. This includes all of the processes that affect the absorption, distribution, metabolism, and excretion along with any toxic side effects. Due to the high cost and enormous experimental effort involved, complete pharmacokinetic and toxicity studies can only be carried out on a small number of drug development candidates. A variety of test methods have been developed to correlate chemical structure with ADME and toxicological properties. A drug must cross multiple lipid membrane barriers and aqueous compartments on its way from the site of application to the site of the target protein. Adequate lipophilicity is described by the partition coefficient between lipid/water phase. In the simplest model, the partition between octanol and water is measured. More sophisticated models have been developed to relate chemical structure to penetration properties. Particularly important are considerations regarding the release of the water solvating shell around a drug molecule and its potential to form hydrogen bonds when crossing lipid membranes. Many drugs are either weak acids or bases. Depending on the pH applied, they will exist in either a more lipophilic neutral form or a more polar ionized form. The membrane penetration of such species is therefore highly dependent on the local pH conditions. Due to the progressively changing pH conditions in the stomach and intestine, at some point along the gastrointestinal tract, appropriate pH conditions exist that allow sufficient penetration of the neutral form. Due to established equilibria, small amounts of the neutral form of an acidic or basic drug molecule are the intermediate through which membrane penetration occurs. The dissociation equilibrium rapidly replenishes the constant removal of the neutral species from the aqueous phase into the membrane. Adjusting lipophilicity is critical to pharmacokinetics. Typically, the more lipophilic a compound is, the better it is absorbed; however, limited solubility in water limits lipophilicity. Appropriate test models have been developed using thin layers of human colon cells. These also allow the study of absorption by transporters. Compounds are initially tested in simple in vitro test models. Cellular assays will gradually be used in animal models. Relevant activity-activity relationships must be established to correlate response in animal models. At best, results from appropriate in vivo tests can predict therapeutic effects in humans. Nature works with two orthogonal principles in releasing its native compounds: specificity of biological action and pronounced spatial compartmentalization. Some compounds are highly specific and travel long distances through the organism to exert their action. Others are synthesized locally and stimulate their target protein in the immediate vicinity. Here, high specificity and selectivity are not required. Whether high isoform selectivity or protein family-wide promiscuity is required depends very much on the mode of action and biological function of the targeted protein. Prior to human administration, clinical candidates are tested in animals. When extrapolating from animal to human, it is important to note that test models are highly species dependent. Even metabolism can be very different between humans and different animal species. Estimates of human toxicity must be made from data obtained in other species. Chronic toxicity is routinely determined in two species. It must be evaluated in the species with the closest pharmacokinetic and metabolic similarities to humans. Toxicity often differs by several orders of magnitude. Even the most comprehensive toxicity studies cannot eliminate the risk that, in extremely rare cases, serious adverse effects will occur when a new drug is widely used. The animal studies of the past have been replaced by more conclusive binding studies using membrane homogenates and cell cultures. Whole-animal testing has shifted to lower animals such as pinworms, fruit flies or zebra fish. https://sn.pub/ssi0og