Physiologically-based pharmacokinetic (PBPK) modeling has been extensively used to quantitatively translate in vitro data and evaluate temporal effects from drug-drug interactions (DDIs), arising due to reversible enzyme and transporter inhibition, irreversible time-dependent inhibition, enzyme induction, and/or suppression. PBPK modeling has now gained reasonable acceptance with the regulatory authorities for the cytochrome-P450-mediated DDIs and is routinely used. However, the application of PBPK for transporter-mediated DDIs (tDDI) in drug development is relatively uncommon. Because the predictive performance of PBPK models for tDDI is not well established, here, we represent and discuss examples of PBPK analyses included in regulatory submission (the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA)) across various tDDIs. The goal of this collaborative effort (involving scientists representing 17 pharmaceutical companies in the Consortium and from academia) is to reflect on the use of current databases and models to address tDDIs. This challenges the common perceptions on applications of PBPK for tDDIs and further delves into the requirements to improve such PBPK predictions. This review provides a reflection on the current trends in PBPK modeling for tDDIs and provides a framework to promote continuous use, verification, and improvement in industrialization of the transporter PBPK modeling. ) † Venkatesh Pilla Reddy and Kunal S. Taskar equally contributed to this article and are joint first authors. REVIEW(1)) CL H,int = (PS inf ,act + PS inf,pas ) * (CL int,met + CL int,sec ) PS ef f,act + PS ef f,pas + CL int,met + CL int,sec (3) CL H,int = PS inf * REVIEW
ABSTRACT:Oseltamivir (Tamiflu, Roche, Nutley, NJ), an ester-type prodrug of the anti-influenza drug Ro 64-0802 (oseltamivir carboxylate), has been reported to be associated with neuropsychiatric side effects, which are likely to be caused by distribution of oseltamivir and/or its metabolite into the central nervous system. Enhanced toxicity and brain distribution of oseltamivir in unweaned rats led us to hypothesize that the low level of distribution of oseltamivir and/or Ro 64-0802 in adult brain was caused by the presence of a specific efflux transporter at the blood-brain barrier. We examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance protein 1 P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice. The permeability of oseltamivir in the basal-toapical direction was significantly greater than that in the opposite direction. The directional transport disappeared on addition of cyclosporin A, a P-gp inhibitor. The brain distribution of oseltamivir was increased in mdr1a/1b knockout mice compared with wildtype mice. In contrast, negligible transport of Ro 64-0802 by P-gp was observed in both in vitro and in vivo studies. These results show that oseltamivir, but not Ro 64-0802, is a substrate of P-gp. Accordingly, low levels of P-gp activity or drug-drug interactions at P-gp may lead to enhanced brain accumulation of oseltamivir, and this may in turn account for the central nervous system effects of oseltamivir observed in some patients.Oseltamivir phosphate (oseltamivir) (Fig. 1), manufactured under the trade name Tamiflu (Roche, Nutley, NJ) as an ester-type prodrug of the neuraminidase inhibitor Ro 64 -0802 (oseltamivir carboxylate) (Fig. 1), has been developed for the treatment of A and B strains of the influenza virus, whereas the typical anti-influenza drug amantadine is used only for the A strain. However, the drug exhibits several adverse effects, not only in the digestive system (abdominalgia, diarrhea, and nausea) but also in the central nervous system (CNS); the latter include headache, vertigo, somnolence, insomnia, numbness, and behavioral excitement (basic product information of Tamiflu from Roche). Recently, there has been concern that the drug may be associated with suicidal or abnormal behavior especially in younger patients (http://www.fda.gov/cder/drug/ infopage/tamiflu/QA20051117.htm and http://www.mhlw.go.jp/english/ index.html). At present, the U.S. label of the drug specifies that the drug is not to be administrated to patients less than 1 year of age, whereas the label in Japan only mentions that the safety in the patients is not confirmed and includes the caution that administration to patients older than 10 years of age is possibly at risk to develop neurological side effect.In general, CNS effects are caused by distribution of a drug and/or its metabolite(s) into the CNS through the blood-brain barrier (BBB). When ose...
We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.
The proof of target engagement (TE) is a key element for evaluating potential investment in drug development. The cellular thermal shift assay (CETSA) is expected to facilitate direct measurement of intracellular TE at all stages of drug development. However, there have been no reports of applying this technology to comprehensive animal and clinical studies. This report demonstrates that CETSA can not only quantitatively evaluate the drug-TE in mouse peripheral blood, but also confirm TE in animal tissues exemplified by using the receptor interacting protein 1 kinase (RIPK1) lead compound we have developed. Our established semi-automated system allows evaluation of the structure-activity relationship using native RIPK1 in culture cell lines, and also enables estimation of drug occupancy ratio in mouse peripheral blood mononuclear cells. Moreover, optimized tissue homogenisation enables monitoring of the in vivo drug-TE in spleen and brain. Our results indicate that CETSA methodology will provide an efficient tool for preclinical and clinical drug development.
The present study was designed to identify the organic anion transporting polypeptide (OATP) molecule(s) responsible for the uptake of beta-lactam antibiotics in human liver, using cryopreserved hepatocytes, as well as Xenopus oocytes and cultured cells expressing human OATPs. Nafcillin uptake by human hepatocytes was saturable with a Km of 533 microM. In vitro uptake studies revealed that OATP1B3 and OATP1B1 transported nafcillin with Km values of 74 microM and 11 mM, respectively. Analysis by the relative activity factor method suggested that OATP1B3 contributes mainly to nafcillin uptake and OATP1B1 contributes moderately. This conclusion was supported by the results of a study with selective inhibitors. Furthermore, OATP1B3 transported six other beta-lactam antibiotics, and their uptake clearances by OATP1B3 correlated well with those mediated by rat Oatp1a4, which is the predominant contributor to basolateral uptake of nafcillin by rat hepatocytes. These findings suggest that OATP1B3 plays a major role in the hepatic uptake of beta-lactam antibiotics in humans, and probably corresponds functionally to Oatp1a4 in rat liver.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.