Current Drug Metabolism - Volume 21, Issue 6, 2020

Background: In January 2020, the US FDA published two final guidelines, one entitled “In vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry” and the other entitled “Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry”. These were updated from the 2017 draft in vitro and clinical DDI guidance. Methods: This study is aimed to provide an analysis of the updates along with a comparison of the DDI guidelines published by the European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) along with the current literature. Results: The updates were provided in the final FDA DDI guidelines and explained the rationale of those changes based on the understanding from research and literature. Furthermore, a comparison among the FDA, EMA, and PMDA DDI guidelines are presented in Tables 1, 2 and 3. Conclusion: The new 2020 clinical DDI guidance from the FDA now has even higher harmonization with the guidance (or guidelines) from the EMA and PMDA. A comparison of DDI guidance from the FDA 2017, 2020, EMA, and PMDA on CYP and transporter based DDI, mathematical models, PBPK, and clinical evaluation of DDI is presented in this review.

Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Glycyrrhiza glabra L. (Family: Fabaceae) is one of the important traditional medicinal plant used extensively in folk medicine. It is known for its ethnopharmacological value in curing a wide variety of ailments. Glycyrrhizin, an active compound of G. glabra, possesses anti-inflammatory activity due to which it is mostly used in traditional herbal medicine for the treatment and management of chronic diseases. The present review is focused extensively on the pharmacology, pharmacokinetics, toxicology, and potential effects of Glycyrrhizic Acid (GA). A thorough literature survey was conducted to identify various studies that reported on the GA on PubMed, Science Direct and Google Scholar.

Background: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. Objective: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. Methods: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. Results: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. Conclusion: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

Background: Green tea can inhibit OATPs, so it may interact with the substrate of OATPs, such as rosuvastatin. Objective: This study aimed to investigate the effects of green tea on the pharmacokinetics of rosuvastatin and its mechanism. Methods: Male Sprague-Dawley rats received different doses of green tea extract (GTE) and (-)- epigallocatechin-3- gallate (EGCG). Caco-2 cells and OATP1B1-HEK293T cells were used in drug uptake and transport assay. The matrix concentrations of rosuvastatin and catechins were determined by ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS). Results: GTE and EGCG were both found to increase the area under the plasma concentration-time curve (AUC0-∞) of rosuvastatin ((p<0.050). In the Caco-2 cell model, the uptake and transport of rosuvastatin in the GTE groups were 1.94-fold (p<0.001) and 2.11-fold (p<0.050) higher, respectively, than those of the control group. However, in the EGCG group, the uptake and transport of rosuvastatin were decreased by 22.62% and 44.19%, respectively (p<0.050). In the OATP1B1- HEK293T cell model, the OATP1B1-mediated rosuvastatin uptake was decreased by GTE to 35.02% of that in the control (p<0.050) and was decreased by EGCG to 45.61% of that in the control (p<0.050). Conclusion: GTE increased the systemic rosuvastatin exposure in rats. The mechanism may include an increase in rosuvastatin absorption and a decrease in liver distribution by inhibiting OATP1B1. EGCG may be the main ingredient of green tea that affects the pharmacokinetic parameters of rosuvastatin. Our results showed the importance of conducting green tea-rosuvastatin study.