Identifying and developing a drug product is a very lengthy and costly process. One of the primary reasons for a high rate of drug failure is poor pharmacokinetic properties. Currently, researchers are focused on identifying crucial pharmacokinetic challenges to validate potential drug compounds in the early stages of drug development.
Bioavailability is a fundamental aspect of pharmacokinetic properties. Several bioequivalence services conduct both bioavailability and bioequivalence testing (BABE studies) for large pharmaceutical companies. In vivo bioequivalence clinical trials conduct preliminary in vivo bioequivalence studies to demonstrate that a generic product is bioequivalent to a reference listed drug.
Today many high-throughput and cost-effective in vitro models predicting drug absorption are readily available to evaluate drug transport and permeability across biological membranes. Among them, cell-based and tissue-based are the most used experimental models. Although these methods are not efficient in reflecting human physiological factors, their ethical and financial attributes have made their use successful in the early clinical decision-making processes.
Why opt for preclinical tissue models?
Bioavailability studies employ several in vitro tissue-based experimental models for assessing drug permeability. Although using in vivo animal experimental models for permeability studies produces better results, preclinical tissue models provide several essential benefits over animal models. Some crucial advantages are:
Tissue-based assays require less quantity of drug
No animals or at times just a few are needed
More number of compounds can be analyzed
Metabolism and transport mechanism can be studied
Compared to biological fluids, tissue-based assays are easier to evaluate
In-vitro tissue-based analysis can be carried out at a reduced experimental cost
Reproducible and simple tissue-based models can be a beneficial screening tool for new chemical entities
What are the types of tissue-based models, and how do they work?
There are four main types of tissue-based in vitro models; diffusion chambers, Franz cells, everted sacs, and isolated membrane vesicles. Mostly isolated animal tissues are used in preclinical tissue models. These tissues are arranged in different devices to estimate permeability.
Diffusion chambers quantify transepithelial drug absorption across different tissues. In intestinal permeation, researchers isolate intestinal segments and cut them into flat tissue layers. They then arrange these layers upon buffer-filled diffusion cells to mimic extracellular fluids.
Franz diffusion cells are great at in vivo skin permeation. These systems consist of a skin-like membrane, separating the acceptor and donor compartments. The membranes are of animal, human or artificial origin.
Everted sacs are heavily used in studying the accumulation of drugs in intestinal segments. Researchers invert and divide the intestinal parts into smaller sections and incubate them with a suitable oxygenated sample, with regulated temperature and agitation conditions. Everted sacs help access drug retention in tissues.
Isolated membrane vesicles are obtained from basolateral membrane vesicles or the brush border of enterocytes. Vesicle preparation goes through tissue homogenization, differential sedimentation, and fractionation steps. They are widely used for evaluating the transcellular transport of pharmaceutical compounds.
The road ahead
Several factors influence the working of tissue-based preclinical models. Most of these factors are associated with pre-,post-experimental, and study conditions. Thus adequate standardization of tissue-based models can help reduce variability observed in permeability values.