Pharmacokinetics drug disposition

Experience has shown that the exploratory profiling of the impact of gender, high age, and food intake (in the form of a food screen for worst case food effects) on drug disposition (pharmacokinetics) and safety can be conveniently done in one study with the design described in this article. If a notable effect of these parameters is/are seen, then confirmatory studies need to be performed. 

Importantly, the currently available transporter models only cover a small fraction of all transporters involved in drug disposition. Other than incorporating current stand-alone transporter models into systemic models to directly predict drug pharmacokinetic properties, continued efforts are still needed to investigate other transporters such as MRP, BCRP, NTCP, and OAT, to get a more complete understanding of the drug pharmacokinetic profile. 

Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci 2002 May 91(5) 1358-70. 

Ward et al. [125] investigated the disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation, after the administration of 0.5, 1.5, and 5 mg doses of the drug. The pharmacokinetics of primaquine in the experimental model was dependent on dose size. Increasing the dose from 0.5 to 5 mg produced a significant reduction in clearance from 11.6 to 2.9 mL/min. This decrease was accompanied by a disproportionate increase in the value of the area under the curve from 25.4 to 1128.6 pg/mL, elimination half-life from 33.2 to 413 min, and volume of distribution from 547.7 to 1489 mL. Primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected perfusate after the 0.5 mg dose, it was the principal perfusate metabolite after 5 mg dose. Primaquine was subject to extensive biliary excretion at all doses, the total amount of 14C-radioactivity excreted in the bile decreased from 60 to 30%i as the dose of primaquine was increased from 0.5 to 5 mg. 

Drug disposition parameters can be estimated if the relationship between the pharmacokinetic parameters of the drug and renal function are known. 

From Cusack BJ. Pharmacokinetics in older persons. Am J Geriatr Pharm 2004 2 274-302 and Chapron DJ. Drug disposition and response. In Delafuente JQ Stewart RB, eds. Therapeutics in the Elderly 3rd ed. Cincinnati, OH Harvey Whitney, 2000 257-288. 

Tse, F.L.S. and Jaffe, J.M. (1991). Preclinical Drug Disposition. Marcel Dekker, New York. Vinegar, A. and Jepson, G. (1996). Cardiac sensitization thresholds of halon replacement chemicals in humans by physiologically based pharmacokinetic modeling. Risk Analysis 16 571-579. 

Table 1 Comparison of Predicted Pharmacokinetic Parameters for Two Different Drugs with Identical In Vitro Drug Release Profiles, But Different Drug Disposition Characteristics (ty2 = 1 or 6 hr)...

A. Black, T. Chang, Metabolic Disposition of Roliziracetam in Laboratory Animals , Eur. J. Drug Metab. Pharmacokinet. 1987, 12, 135-143. 

There is a diversity of opinion regarding definitions and benefits of pharmacogenetics and pharmacogenomics.1 3 For example, pharmacogenetics is often considered to be the study of inter-individual variations in DNA sequence related to drug absorption and disposition (pharmacokinetics, PK) or drug action (pharmacodynamics, PD). Polymorphic variation in the genes that encode the functions of transporters,... 

Pharmacokinetics (PK) can be defined as the study of the mechanisms and kinetics of drug disposition in the body (acronym LADME ), and includes the following ... 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Fig. 5. Selection of candidate genes for selection in a either a study examining the role of pharmacogenomics in drug disposition and/or action or alternatively, use as a chnical tool to individualize drug therapy. Those genes prioritized for inclusion should he those shown to contribute markedly to drug pharmacokinetics and/or dynamics.

Comprehensive knowledge of the clinical pharmacology (e.g., concentration-effect relationships, pharmacokinetic and pharmacodynamic profile, information related to altered drug disposition and/or action consequent to development, disease, concomitant drug therapy) for the drug(s) of interest... 

This chapter will give a basic overview of pharmacokinetics and development. The review should allow clinicians to better understand drug disposition issues so as to inform their ordering and interpretation of TDM, as well as help them to understand or design and interpret clinical drug trials. 

DEVELOPMENTAL FAQORS AFFEaiNG DRUG DISPOSITION AND PHARMACOKINETIC... 

Wilson CL, Babb TL, Halgren E, et al Habituation of human limbic neuronal response to sensory stimulation. Exp Neurol 84 74-97, 1984 Wilson K Sex-related differences in drug disposition in man. Clin Pharmacokinet 9 189-202, 1984... 

Pharmacokinetics and pharmacodynamics form the two major branches of pharmacoiogy. Pharmacokinetics is the study of drug disposition and deais with the processes of absorption, distribution, metaboiism and eiimination. Pharmacodynamics is concerned with the reiationship between the concentration of a drug and its effect. Put another way, pharmacodynamics is what a drug does to the body whiie pharmacokinetics is what the body does to a drug. This chapter wiii cover the generai principies reiating to these processes, and deveiop some of the principies that describe their kinetics and dynamics. 

Compartmental models are commonly used in pharmacokinetics to explain drug disposition. 

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