Pharmacokinetic defects

Drug disposition and metabolism are of essential significance in pharmaceutical research because of the interdependence of pharmacokinetic and pharmacodynamic processes. Limited intestinal absorption, inadequate distribution, fast metabolism, and toxic metabolites are some of the causes of failure of drug candidates during development. To reduce the rate of attrition resulting from such pharmacokinetic defects, disposition and metabolic studies should be initiated as early as possible in the screening of lead candidates. 

A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

Eichelbaum, M., Spannbrucker, N. and Dengler, H.J. (1979) Influence of the defective metabolism of sparteine on its pharmacokinetics. European Journal... 

LD50 is a measure of acute toxicity. Over time, many other test requirements have been added to establish safety as shown in the safety decision tree developed by the Food Safety Council (1982). In this system an organized sequence of tests is prescribed (see Figure 12-1). Other tests in this system involve genetic toxicity, metabolism, pharmacokinetics (the pathways of chemicals in the system and their possible accumulation in organs), subchronic toxicity, teratogenicity (birth defects), and chronic toxicity. To all this are added tests for carcinogenicity and... 

Pharmacokinetic information that relates blood concentration to toxic response is critical in defining such dose-response relationships, but information on peak blood concentrations or blood concentrations over time (area under the curve (AUC)) is seldom available. One agent for which such information has been published is 2-methoxyacetic acid (2-MAA), the active metabolite of 2-methoxyethanol. Terry et al. (1994) showed that peak concentration was related to neural tube defects observed after exposure in mice on gestation day 8, whereas area under the curve was shown to be related to limb defects after exposure to 2-MAA on gestation day 11 (Clarke et al. 1992), suggesting that the time of exposure and pattern of development of the susceptible organ... 

Radhofer-Welte and Dittrich [35] described a rapid and sensitive HPLC method for the determination of lornoxicam in plasma samples of humans and laboratory animals. After addition of the internal standard, tenoxicam, the plasma was acidified and extracted by dichloro-methane via Extrelut columns or by solid-phase extraction using Cis columns. After evaporation of fhe solvenf, fhe separation is performed on a Ci8 column in isocratic mode wifh a mobile phase consisting of 0.1 M phosphafe buffer (pH 6)-methanol, and defection at 372 nm. The limit of deferminafion was set to 10 ng/ml using 0.5 ml of sample but can be extended down to 2 ng/ml plasma. Using solid-phase extraction with Cis columns both lornoxicam and its main metabolite 5 -hydroxylornoxicam can be determined while extraction via Extrelut was used in studies where only lornoxicam was to be determined. The method was used in several thousand samples of pharmacokinetics and bioavailability studies in animals and humans. 

A widely available fixed combination is co-trimoxazole (Bactrim, Eusaprim, Septrin), which contains trimethoprim and sulfamethoxazole in a ratio of 1 5. Both trimethoprim and sulfamethoxazole have favorable and comparable pharmacokinetics and the combination is bactericidal (4). Synergy between trimethoprim and sulfonamides has conventionally been ascribed to sequential inhibition of dihydropteroate synthetase by sulfonamides (in competition with pora-aminobenzoic acid) and of dihydrofolate reductase by trimethoprim (in competition with dihydrofolate). However, sulfonamides in high concentrations also inhibit dihydrofolate reductase. Thus, an initial partial sequential blockade by trimethoprim (inhibition of dihydrofolate reductase) and sulfonamides (inhibition of dihydropteroate synthetase) leads to defective protein synthesis and cytoplasmic damage, which in turn results in marked increases in the uptake of both agents and double strength inhibition of dihydrofolate reductase (5). 

Eichelbaum M, Spannbrucker N, Dengler HJ. Influence of the defective metabohsm of sparteine on its pharmacokinetics. Eur J Clin Pharmacol 1979 16 189-94. 

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