Active transport, pharmacokinetics

The processes of pharmacokinetics all involve the transfer of a drug across membranes, beginning with the cell membrane, and sometimes involving single or multiple layers of cells. Drugs can cross these membranes through passive or active transport. 

Active transporters are thought to play an important role in the pharmacokinetics of drugs, not only because they can regulate the permeability of drugs as substrate-specific efflux or influx pumps, but also because of their widespread presence across in vivo membrane systems, from the intestinal epithelia to the BBB. Generally speaking, the absorption direction transporters tend to have narrower substrate specificity than the excretion direction transporters. Active transporters also play a significant role in biliary and renal excretion. 

Some caution is required with some chemical classes and compound properties related to low solubility, high lipophihcity, major impact of active transport processes on elimination and distribution. It is therefore recommended that PBPK models should only be applied after verification of the simulations with in vivo pharmacokinetics for a few compounds of a given chemical class. Such verification will help to identify invalid model assumptions or missing processes where additional data is needed. 

Pharmacokinetics Well absorbed from the G1 tract. Enters cells by active transport from extracellular fluid. Primarily excreted in urine. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

Enantiomers also are referred to as chiral compounds, antipodes, or enantiomorphs. When introduced into an asymmetric, or chiral, environment, such as the human body, enantiomers will display different physicochemical properties, producing significant differences in their pharmacokinetic and pharmacodynamic behavior. Such differences can result in adverse side effects or toxicity, because one or more of the isomers may exhibit significant differences in absorption (especially active transport), serum protein binding, and metabolism. With the latter, one isomer may be converted into a toxic substance or may influence the metabolism of another drug. To discuss further the influence of stereochemistry on drug action, some of the basic concepts of stereochemistry need to be reviewed. 

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