SOME PHARMACOKINETIC CONSIDERATIONS

The residues in edible products of treated animals do not necessarily constitute the pharmaceutical compounds initially administered to the animals. They may consist of various components including the parent compound and/or free metabolites, and metabolites covalently bound to macromolecules. 

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Levy G. Targeted drug delivery—some pharmacokinetic considerations. Pharm Res 1987 4 3-4. 

Some Pharmacokinetic Considerations of Biotechnology-Produced Proteins... 

KB Bischoff. Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy. Cancer Chemother Rep 59 777-793, 1975. 

Although metoclopramide has lost some ground to newer congeners, it has been the most widely used of the neuroleptic-type antiemetic drugs and is therefore the one for which the clearest picture of adverse effect, typically neuroleptic and endocrine effects, has emerged. Reactions are generally short-lived provided treatment is withdrawn the duration of reactions does not always seem to be explained by simple pharmacokinetic considerations. 

This clearly indicates that the nature of the bond between the carrier and the active moiety plays a major role in prodrug design and that pharmacokinetic considerations are of utmost importance in this context. In the following paragraphs, some typical kinds of chemical bonds are discussed. It is not intended here to present an overview on this subject, but only to give some examples of how chemistry and pharmacokinetics interact in the field of prodrugs. 

Acylation of 6-APA with appropriate substances results in new penicillins being produeed whieh differ only in the nature of the side chain (Table 5.1 Fig. 5.2). Some of these penieillins have considerable activity against Gram-negative as well as Grampositive baeteria, and are thus broad-spectrum antibiotics. Pharmacokinetic properties may also be altered. 

The success of any drug delivery system depends upon how it interacts with the biological system to deliver its drug at the optimum rate and at the site where it is needed. This paper discusses some of the considerations that must be made in developing successful drug delivery systems and the opportunities available if a comprehensive assessment is made of the pharmacology, pharmacokinetics, and pharmacodynamics involved. 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

Solution equilibria for gadolinium imaging agents have been studied with consideration for pharmacokinetic, protein binding, elimination, and safety aspects of the dmgs. The thermodynamic stability constant, Kq defined by equation 7.4 must be large for clinically viable agents. Some Kq l data are listed in Table 7.3. 

The adjustment of dose and dosing regimen for children and the elderly needs a special consideration because of several differences as compared to an adult individual. The differences may be due to many factors which include changes in pharmacokinetic parameters, age, body weight, surface area, and genetic predisposition. The present chapter provides some basic explanation about their differences and the dosage calculations because of these differences. 

The closely related herbicides have some differences in distribution and pharmacokinetics which are largely resolved by returning to the observation above that the water solubility of 2,4-D is about 3-fold greater than that of 2,4,5-T. Thus, 2,4-D has initial and final t., values as well as clearance value, about 3 times those founa for 2,4,5-T. These data all fit with the major distribution difference of these 2 compounds, i.e., that considerably more of the dose of 2,4-D is excreted in the urine in 24 hrs. 

The serendipitous discovery of the antitumor activity of cisplatin opened a huge field of research, leading to significant advances and successes in cancer chemotherapy [181]. Cisplatin and its analogues are reactive complexes that exhibit pharmacokinetic, pharmacodynamic, and toxicological behaviors so closely interdependent as to be all but impossible to untangle. Our focus here is and remains metabolism, but some considerations regarding activity and toxicity are also addressed. 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

Even in people with the same diagnosis and the same inclusion and exclusion criteria, there are different treatment responses based on individual variability. The most important individual variables are probably sex and age. It is unfortunate that even though affective disorders and some anxiety disorders are more prevalent in women than in men, until recently results of clinical trials did not take into consideration sex differences and variables unique to women [e.g., reproductive status and menstrual cycle]. As is demonstrated by Yonkers et al. [see Chapter 5, in this volume], there are substantial sex differences in the pharmacokinetics and pharmacodynamics of most antidepressants and anxiolytics, which influence treatment response. Attention to these variables will indeed improve the efficacy of treatment. 

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