Physiological Biological Principles Pharmacokinetics

The other broad discipline in biopharmaceutics is PK, which is the study of the time course of ADME (Gibaldi and Perrier, 1982; Rowland and Tozer, 1989). Just as the physical-chemical and formulation principles are intimately linked with the pharmacokinetic profile, the PK profile is directly related to the pharmacologic activity of a drug. For the purpose of this discussion, we will use PK and ADME interchangeably.


In most cases, a drug must be absorbed across a biological membrane in order to reach the general circulation and/or elicit a pharmacologic response. Even drugs that are dosed intravenously may need to cross the vascular endothelium to reach the target tissue or distribute into blood cells. Often multiple membranes are encountered as a drug traverses the absorptive layer and diffuses into the blood stream. Transport across these membranes is a complex process, impacted by ionization equilibria, partitioning into and diffusion across a lipophilic membrane and potential interaction with transporter systems (influx and/or efflux).

Membrane transport can occur either passively or actively (Rowland and Tozer, 1989). Passive transport (diffusion) is the movement of molecules from a region of high concentration to one of low concentration. The membrane permeability, which is directly related to the relative lipophilicity of the drug, is a major factor affecting the rate and extent of absorption for a given compound, and for GI

absorption the concentration gradient is related to the solubility of the compound in the intestinal brush border microenvironment (Rowland and Tozer, 1989).

Active transport is an energy-consuming process whereby membrane-bound transporters bind and transport materials across membranes, even against a concentration gradient. Physiologically, these active transporters exist to promote absorption of nutrients and hence are typically related to food substances such as peptides, amino acids, carbohydrates, and vitamins. They can lead to absorption efficiency that is significantly greater than what would be predicted based on a passive diffusion mechanism. In recent years many of these transporters have been characterized with respect to structure, cellular location, and substrate specificity (Katsura and Inui, 2003; Sai, 2005). Conversely, active transport mechanisms also exist to transport materials out of cells (efflux pumps). The most well-studied efflux pumps are in the class of ATP-binding cassette (ABC) transporter proteins, including p-glycoprotein (P-gp) and the multidrug resistance protein (MRP) family (Kivisto et al., 2004; Leslie et al., 2005). These natural transporters are cellular defenses that exist to prevent entry of unwanted potentially toxic materials into the systemic circulation, and they can also work against the movement of drug molecules. The reader is referred to Chap. 7, which discusses role of such transporters in absorption processes in detail.

The concepts of permeability, absorption, and bioavailability (BA) are sometimes used interchangeably, while in fact each represents a different aspect related to membrane transport. Permeability refers to the ability of a compound to cross a membrane. A permeable compound may diffuse across the intestinal epithelium only to be actively transported out of the cell. This compound is permeable, yet not absorbed. Likewise, a drug may pass through the intestinal epithelium, indicating absorption, yet be metabolized in the gut wall or the liver prior to reaching the peripheral circulation. This drug is absorbed, yet it is not bioavailable. The relevance of this will be discussed in subsequent Chaps. 4 and 5.


Distribution is a measure of the relative concentrations of a drug in different body tissues as a function of time (Rowland and Tozer, 1989) and is related to its ability to diffuse from the blood stream, tissue perfusion, relative lipophilicity, and tissue/plasma protein binding. The apparent volume of distribution (Vd) is reflective of the extent of tissue distribution. Drug distribution in vivo is often related to the drug's chemical structure. It can be measured and manipulated during the course of compound optimization by addition or deletion of certain functional groups or structural features. However, formulations typically cannot have significant impact on a drug's distribution properties without chemical alterations such as conjugation or use of specific drug targeting technology.

Metabolism and Elimination

Metabolism is one of the most important mechanisms that the body has for detoxifying and eliminating drugs and other foreign substances. Drugs delivered by the oral route must pass through the liver before reaching the general circulation.

Metabolism at this point is called "first-pass metabolism," which can limit systemic exposure for drugs despite good absorption. Oxidation, reduction, hydrolysis, and conjugation are the most common metabolic pathways, generally leading to more hydrophilic compounds that can be readily excreted renally. Cytochrome P450 (CYP) enzymes are a family of drug metabolizing enzymes that are responsible for the majority of drugs' metabolism as well as many drug-drug interactions (Shou et al., 2001; Meyer, 1996). Although the primary role of metabolism is to facilitate elimination of drugs from the body, secondary effects include transformation of drugs into other active or toxic species, which could be desirable in the case of prodrugs (Stella et al., 1985) or undesirable with respect to toxic metabolites (Kalgutkar et al., 2005). The reader is encouraged to refer to authoritative texts in this field.

Elimination of drugs from the body can occur via metabolism, excretion (renal, biliary, respiratory), or a combination of both mechanisms. As with distribution, these phases of the drug's PK profile are inherent to the chemical structure of the drug and are optimized (along with pharmacologic potency and fundamental safety) during the drug discovery process.

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