Recalling P446. P4501A1 (CYP1A1) opting for clinical application.

This review goes back to spectral studies [see Hildebrandt et al., 1968]. The findings of apparent absolute spectra of two interconvertible forms of microsomal mixed function oxidases are looked back on to recall whether their impact sustained scrutiny or are rather remembered as of sentimental value only. The second part summarizes studies on the clinical relevance of CYP1A1 with special reference to our investigations. The impact of genetic variability of CYP1A1 on cancer susceptibility, differential effects of polyphenols and hyperforin on toxification and detoxification pathways of benzo[a]pyrene, and differential metabolite patterns of 17 beta-estradiol, estrone, and eicosapentaenoic acid are presented.

Pharmacogenetics-based new therapeutic concepts.

Pharmacogenetics, one of the fields of clinical pharmacology, studies how genetic factors influence drug response. If hereditary traits are taken into account appropriately before starting drug treatment, the type of drug and its dosage can be tailored to the individual patient's needs. Pharmacogenetics adds a considerable amount of stringency to the doctor's therapeutic approach. Today, it is the relationship between dosage requirements and genetic variations in drug metabolizing enzymes like cytochrome P450 (CYP) 2D6 and CYP2C19, or in drug transporters like p-glycoprotein, that is substantiated best. A standard dose will bring about more adverse effects than usual if enzymatic activity is lacking or feeble. Sometimes, however, therapeutic response might be better due to higher concentrations: proton pump inhibitors for eradication of Helicobacter pylori are more efficacious in carriers of a deficient CYP2C19 variant. The drug's interaction with its target (e.g. receptor) also depends on genetic factors. In some cases genetic tests can help distinguish between responders and non-responders of a specific drug treatment. The first pharmacogenetic tests are already on the market.

Pharmacology, drug efficacy, and the individual.

The efficacy of drugs has to be demonstrated following the principal approach of statistical evaluation in controlled clinical trials. This scientifically and internationally accepted numerical approach has developed over the years to its importance, in contrast to the more pharmacologically attempt to extrapolate human efficacy of drugs from data obtained in animal experiments or, to the so-called physiological medicine, which did not allow to delineate the suitability of drugs from a given collective to the individual patient. The requirements for the clinical trial are not always met, especially not with so-called surrogate markers. In addition, concerns exist now as ever that the numerically based approach leads to average drugs and information for the "responsible adult" only, to the debit of the individual patient. The concern does not mind the clinical trial as such, which principally can be tailored to the individual as applied with pharmacogenetics. On the other hand, an unbearable situation of increased efforts towards individualization, drug tailoring, and neglect of treatment for patients with neglected diseases, respectively, is immense. The contribution of the pharmacologists is, to present those detailed information which allow proper judgement for the clinical application of drugs for all patients.