Simulation of CYP3A4‐mediated Metabolic Interactions of 1α,25‐Dihydroxyvitamin D3 with Selected Kinase Inhibitors
Authors: Deb Subrata , Hagemann Hayden 
Published: June 2021

Introduction

Lower plasma levels of 1α,25‐dihydroxyvitamin D3 (calcitriol) are associated with increased risk of prostate, colon, and breast cancer. Calcitriol is the active form of vitamin D3 and is metabolized by cytochrome P450 3A4 (CYP3A4). The epidermal growth factor receptor (EGFR)‐related kinase and other kinase enzymes play a critical role in prostate cancer development and progression. Kinase inhibitors (e.g. dasatinib, imatinib) are a class of investigational drugs for prostate cancer and currently being used in other hormonal cancers such as breast cancer. Interestingly, some of the kinase agents have the potential to inhibit CYP3A4 as well. We hypothesize that kinase inhibitors will augment calcitriol levels in humans following blockade of CYP3A4‐mediated calcitriol metabolism. The objective of the present study was to simulate the metabolic interaction of kinase inhibitors and calcitriol using GastroPlus software to predict their in vitro/in vivo interaction potential.

Methods

PKPlus™, ADMET Predictor™ and Drug‐Drug Interaction (DDI)™ modules of GastroPlus software 9.5 version (Simulations Plus, Inc., Lancaster, CA) were used to simulate the metabolic interaction of calcitriol and kinase inhibitors. The metabolism and pharmacokinetic (PK) parameters of calcitriol were obtained from previously published work of the investigator or from PubMed. The physicochemical properties and structures of the kinase inhibitors were collected from PubChem to input into GastroPlus software. The ADMET™ predictor module was used to simulate the structure‐based ADMET properties of kinase inhibitors such as logP, solubility, pKa etc. The PKPlus module used ADMET and PubChem physicochemical data to predict the PK parameters including bioavailability (F%), maximum plasma concentration (Cmax), area under the curve (AUC) and half‐life (t1/2). The DDI module incorporated data from the PKPlus and ADMET predictor module to simulate drug‐drug interactions between calcitriol and six kinase inhibitors (cabozantinib, dasatinib, imatinib, nilotinib, sorafenib, sunitinib).

Results

The ADMET analyses of kinase inhibitors demonstrated that they have a predicted log P value range of 3.0–5.1, whereas they are basic in nature (predicted pKa 10.8–13.1). As such kinase inhibitors have a low predicted solubility of up to 0.3 mg/mL. The PK parameters of kinase inhibitors indicated that the bioavailability ranged from 43–83%, whereas AUC range was 1.5–10.4 ug.h/mL. The PK properties of the kinase inhibitors typically corresponded with their physicochemical properties. The simulation of PKPlus data in DDI module predicted that the kinase inhibitors can block the function of CYP3A4 and have the ability to cause moderate to strong (except imatinib which has weak potential) interaction with calcitriol.

Conclusions

GastroPlus software modules have been highly efficient in generating the physicochemical properties and PK parameters of kinase inhibitors and finally in predicting the drug interaction potential with calcitriol. Calcitriol, which has low oral absorption potential, may experience increased plasma levels when used in combination with a kinase inhibitor. Four of the six kinase inhibitors simulated were found to have a strong in silico interaction with calcitriol. Finally, this suggests that kinase inhibitors may inhibit the metabolism of calcitriol and influence its plasma levels, leading to improved anti‐cancer outcome from calcitriol.

Support or Funding Information

The GastroPlus software 9.5 version was provided by Simulations Plus, Inc. (Lancaster, CA)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.