全部

Analysis of pregnane X receptor (PXR, NR1I2) activation to determine induction of drug metabolizing enzymes and transporters and predict drug-drug interactions (DDIs) is a wildly used technique among in vitro assays. Direct assessment of PXR activation is a cell-based assay that requi ...

As the closest relative of the aforementioned PXR, the constitutive androstane/activator receptor (CAR, NR1I3) also governs the transcription of numerous hepatic drug-metabolizing enzymes and transporters in response to various xenobiotic exposures. Unlike most prototy ...

The Ah receptor (AhR) is a ligand-dependent transcription factor that mediates a wide range of biological and toxicological effects from exposure to structurally diverse synthetic and naturally occurring chemicals. The role of the AhR and its signaling pathway in endogenous physio ...

Time-dependent inhibition (TDI) is an important consideration in the drug development process. To date, methods to accurately predict the magnitude of a clinical interaction from pre-clinical TDI data have been lacking. Although more complex prediction algorithms have been devel ...

This chapter provides a step-by-step description of methodology used to assess time-dependent inhibition/inactivation (TDI) potential of cytochrome P450 3A4 (CYP3A4) by a test compound using human hepatocytes in a 96-well plate format. Human hepatocytes in suspension or plated cu ...

Induction potential of compounds towards CYP1A2, 2B6 and 3A4 via the aryl hydrocarbon (AhR), constitutive androstane (CAR), and pregnane X (PXR) nuclear receptors (NRs), respectively, is routinely determined during small molecule drug development. Significant CYP induction can r ...

In this chapter we have provided a step-by-step protocol of a 384-well plate fluorescence-based assay used for rapid identification of reversible and time-dependent CYP450 inhibition. This was accomplished by comparing the time-dependence pattern of IC50 values of potential test i ...

Cytochrome P450s (CYPs) are responsible for the metabolism of a majority of marketed drugs and, as a consequence, alteration in CYP activity can result in clinically relevant drug-drug interactions (DDIs). Drugs that are time dependent inhibitors (TDIs) of CYPs have been reported to cause s ...

In this chapter we have provided a step-by-step protocol for a time-dependent inhibition (TDI) IC50 shift assay using stable isotopic labeled probe substrates. The assay is performed in a 96-well format and can be fully automated and extended to a 384-well format if desired. Since the IC50 shift ass ...

P-glycoprotein (P-gp), the product of the human ABCB1 gene and often called MDR1, is the best understood membrane protein known to be involved in the active transport of drugs across biological membranes. In addition to mediating or limiting the absorption, distribution, excretion, and tox ...

The correct formulation of new drug candidate compounds in drug discovery is mandatory since the majority of go/no-go decisions to advance candidates are based on in vitro ADME, receptor binding, in vivo pharmacokinetic and efficacy screens. For this reason, having a rapid formulation scr ...

The organ distribution and substrate specificity of breast cancer resistance protein (BCRP), the product of the human ABCG2 gene, overlaps considerably with that of P-glycoprotein. Both are up-regulated in some cancers, leading to drug resistance, and can mediate drug-drug interact ...

A road map to develop ophthalmic formulations for topical ocular applications is provided in this chapter. This includes design of appropriate studies, development of formulations matching target product profile, selection of suitable packaging, stability assessment, and cr ...

A large number of factors are important in conducting anti-glaucoma drug efficacy studies. It is essential to have an understanding of aqueous humor dynamics and how the tonometer, tonometrist, and animal may affect IOP estimates. Additional critical considerations in the design of an an ...

Ocular toxicology pertains to toxicologic effects of drugs administered topically, intraocularly, or systemically. It should also include evaluation of adverse effects of ophthalmic devices such as contact lenses, intraocular lenses, and glaucoma implants. The ophthalmic e ...

Bioanalysis (quantification of drug/metabolite residue in biological fluids and tissues) plays an important role in support of drug efficacy and safety studies during drug development. Bioanalysis can be very challenging when the drug or the metabolites to be measured are unstable or ...

The eye is unique in being composed of different types of structures with various functions. One needs to be aware of these unique aspects and changes due to spontaneous, iatrogenic, or environmental conditions in order to detect toxicologic ocular changes. Since most ocular structures can be ...

This chapter focuses on the test methods necessary to demonstrate the safety and “biocompatibility” of ocular medical devices. Biocompatibility has a variety of definitions, but in general it is the quality of the medical device or biomaterial to not have toxic, adverse, or injurious effec ...

The process of bringing a drug through early development and on through a successful clinical trials campaign is long and complex. This chapter provides an overview of the drug development process and some of the challenges and pitfalls that can be encountered on the path to marketing approval f ...

Selection of appropriate animal models for ocular research is essential to enhance validity of results and to minimize number of animals used. Knowledge of differences in ocular anatomy and physiology of the various animal models is one of the most important parameters in study design. In add ...