**Preface to "Drug–Drug Interactions"**

Drug–drug interactions (DDIs) cause a drug to affect other drugs, leading to reduced drug efficacy or increased toxicity of the affected drug. Some well-known interactions are known to be the cause of adverse drug reactions (ADRs) that are life threatening to the patient. Traditionally, DDI have been evaluated around the selective action of drugs on specific CYP enzymes. The interaction of drugs with CYP remains very important in drug interactions but, recently, other important mechanisms have also been studied as contributing to drug interaction including transport- or UDP-glucuronyltransferase as a Phase II reaction-mediated DDI. In addition, novel mechanisms of regulating DDIs can also be suggested. In the case of the substance targeted for interaction, not only the DDIs but also the herb–drug or food–drug interactions have been reported to be clinically relevant in terms of adverse side effects.

This Special Issue serves to highlight the current progress in research on drug–drug interactions and contains eleven outstanding research articles and five review articles. Firstly are the results of in vitro, animal, and human evaluations of drug–drug interactions and herb–drug interactions that induce representative changes in CYP activity. In addition, the results of studies on DDIs that may occur depending on the transporter, plasma protein binding, and human genotype are included. Practical research results on DDI evaluation using In Silico Prediction and Pharmacovigilance Database are presented. This Special Issue contains results related to the main mechanisms by which DDIs can cause ADRs. In the review article, the DDIs and their relation to CYP1A is systematically arranged, and findings related to the role of CYP in mechanism-based inhibition in clinical settings are summarized. As additional insightful content, the interaction of monoclonal antibodies, the occurrence of DDI according to systemic and local tissue exposure, and the effects of OATP1B1 and 1B3 on DDI are systematically reviewed.

This Special Issue aims to highlight current progress in understanding the drug interactions of commercial drugs, both clinically and nonclinically, and in new discoveries regarding the mechanisms of drug interactions that cause ADR. We expect that this Special Issue will provide insights into drug–drug interactions related to adverse drug reactions and contribute to advancement of the relevant research areas.

> **Dong Hyun Kim, Sangkyu Lee** *Editors*

*Article*

#### **E**ff**ect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats**

**Young-Guk Na** †**, Jin-Ju Byeon** †**, Hyun Wook Huh, Min-Ki Kim, Young G. Shin, Hong-Ki Lee \* and Cheong-Weon Cho \***

College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99, Daehak-ro, Yuseong-gu, Daejeon 34134, Korea

**\*** Correspondence: dvmlhk@gmail.com (H.-K.L.); chocw@cnu.ac.kr (C.-W.C.); Tel.: +82-42-821-7301 (H.-K.L.); +82-42-821-5934 (C.-W.C.)

† These authors contributed equally to this work.

Received: 26 June 2019; Accepted: 17 July 2019; Published: 20 July 2019

**Abstract:** Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.

**Keywords:** tadalafil; ticagrelor; drug-drug interaction; pharmacokinetics; plasma concentration; CYP3A4
