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Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC

Background and objective: Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential. Method: The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between proton pump inhibitors and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4. Results: Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1′-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86μM and 9.71μM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30μM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib, whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism. Conclusion: Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals.

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human induced pluripotent stem cell-derived kidney organoids with SARS-CoV-2. Single cell RNA-sequencing indicated injury and dedifferentiation of infected cells with activation of pro-fibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in Long-COVID., Graphical Abstract, Jansen, Reimer, Nagai et al report that SARS-CoV-2 infects kidney cells and is associated with kidney fibrosis in patients. Using single cell transcriptomics of infected kidney organoids, they show that SARS-CoV-2 causes kidney injury and stimulates pro-fibrotic signaling. Viral infection in organoids was inhibited by a recently developed protease blocker.

The in vitro metabolism and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low solubility (10μM) and was highly permeable (>200nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metabolism of the compound. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94–98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (

Definitive plasma protein binding (PB) studies in drug development are routinely conducted with radiolabeled material, where the radiochemical purity limits quantitative PB measurement. Recent and emerging regulatory guidances increasingly expect quantitative determination of the fraction unbound (Fu) for key decision making. In the present study, PB of 11 structurally- and therapeutically-diverse drugs spanning the full range of plasma binding was determined by equilibrium dialysis of non-radiolabeled compound and was validated against the respective definitive values obtained by accepted radiolabeled protocols. The extent of plasma binding was in agreement with the radiolabeled studies; however, the methodology reported herein enables reliable quantification of Fu values for highly-bound drugs and is not limited by the radiochemical purity. In order to meet the rigor of a development study, equilibrium dialysis of unlabeled drug must be supported by an appropriately validated bioanalytical method along with studies to determine compound solubility and stability in matrix and dialysis buffer, nonspecific binding to the dialysis device, and ability to achieve equilibrium in the absence of protein. The presented methodology establishes an experimental protocol for definitive PB measurement, which enables quantitative determination of low Fu values, necessary for navigation of new regulatory guidances in clinical drug development.