What Is the Best Strategy for Preclinical Testing of Botanicals? A Critical Perspective

The development of a new drug is generally marked by a number of preclinical investigations in a sequential order with regard to contents and logic. However, ethnopharmacology often uses the "reverse pharmacology" approach, which is based on anecdotal therapeutic effects of plants in ancient texts or based on the empirical knowledge of traditional healers. While this approach could successfully lead to new therapeutic applications by using sophisticated techniques and appropriate bioassays in a logical order, unfortunately there is an exponentially increasing number of reports of pharmacological effects of botanical extracts with insignificant bioactivities obtained in often irrelevant in vitro bioassays. The interpretation based on in vitro data can only be misleading since the pharmacokinetic properties of a compound are ignored, unacceptable high dosages of extracts are tested, or metabolism to inactive metabolites is not considered. Further, many natural products are prodrugs that need to be metabolized in vivo by the intestinal microflora or bymammalian phase I/II metabolism. Frequently, attempts are made to master poor pharmacokinetics by administering the extract intraperitoneally or intravenously, clearly moving away from the traditional oral application. In this review article, it is proposed that preclinical testing strategies of botanicals should start with the in vivo examination of extracts in relevant animal models to substantiate the ethnopharmacological/ ethnopharmaceutical use, followed by bioguided fractionation processes using an adequate in vitro model, further followed by pharmacokinetic studies and final in vivo testing of isolated compounds. With our article we would like to encourage authors, reviewers and editors to implement this strategy for the design of experiments and for the reviewing and editing process of manuscripts.