Tissue Distribution and Pharmacodynamics: A Complicated Relationship

Abstract

With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.

Abnormal presentation of serum micro-nutrients in Wistar rats: consequence of virgin engine oil exposure

“…Agents like ethanol, cyclosporine, and morphine have been identified to be so affected, in which the GI mucosa and the liver remove a significant portion of a toxicant during its passage through these tissues, thereby reducing its systemic availability. According to Lim et al[15], ethanol is known to be oxidized by alcohol dehydrogenase in the gastric mucosa, whereas Lin et al [16] have identified that cyclosporine is re-transferred from the enterocyte into the intestinal lumen by P-glycoprotein (an ATP-dependent xenobiotic transporter) and is also hydroxylated by cytochrome P450 (CYP3A4) in these cells. Morphine on the other hand is glucuronidated in intestinal mucosa and liver, and manganese is taken up from the portal blood into liver and excreted into bile.…”

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

“…As outlined in (34), failure due to pharmacodynamic and toxicological issues is of major concern. To be supportive, physiologically based pharmacokinetic models should provide interfaces for pharmacodynamic or toxicological models (19).…”

“…The equations (3)- (6) can easily be extended, e.g. to account for active transport processes (19,20), linear-or nonlinear metabolism (20,21), binding to other relevant molecules (20,22), including target molecules (19) and downstream effects. This opens the door for a wide range of applications in pharmacokinetics and -dynamics.…”

“…It is specified in terms of differential equations for the drug concentration in erythrocytes (e), plasma (p), interstitial space (i) and cellular space (c), and explicitly allows to model the transfer processes between the different sub-compartments. The choice of sub-compartments is motivated by the availability of physiological data and for pharmacokinetic and pharmacodynamic reasons (11,19,20). For the generic parameterization, drug exchange by passive diffusion, non-saturable distribution processes and the absence of metabolic processes is assumed, as in existing models for predicting tissue partition coefficients (12)(13)(14)16).…”

“…This regards transporters in tissues, e.g. (19), distribution in red blood cells, e.g. (20), the possibility of metabolic processes in diverse tissues, e.g.…”