[Pharmacokinetic and metabolic studies in the development of drugs].

A system basing mainly on pharmacokinetic investigations has been elaborated by the author for the development of new drugs. The main elements of this system are as follows: 1.1. Screening toxicity investigations: Bacterial mutagenesis tests. Mammalian mutagenesis tests (These tests must be supported by kinetic studies in order to prove the exposure of the animals to the drug in negative cases, or to detect the critical plasma concentration of the drug in positive cases.) Cytochrome P-450 induction studies. In vitro metabolism studies (Incubation of a drug under development with rat, mouse, dog, rabbit and human liver microsomes (S9 fraction) can show the species (dis) similarities of the drugs. In vitro toxicology studies (The use of tissue cultures may answer the mechanism of toxicity. Early in vitro (eye and skin) irritation studies are of primary importance in the development of topical preparations. Acute toxicology studies (Acute toxicity investigations seem to become less important). 28 days (14 days) toxicity testing with pharmacokinetic measurements. 1.2. Long term and reproductive toxicity testing: The scientifically based evaluation of long term and reproductive toxicity studies can only be made in the light of toxicokinetic and metabolism data. 1.3. Human safety studies. Phase I. Study. The pharmacokinetic measurements must be made in order to see the (non) linearity of the kinetics as the function of dose. Phase II. Study. Pharmacokinetic measurements are necessary in order to establish the effective plasma (blood, serum) concentration of the drug. The pharmacokinetics of the drug should be determined in renal and liver patients, and in most of the cases in healthy elderly people.