Xenobiotica; the fate of foreign compounds in biological systems
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1. Until recently, when drugs were used in critically ill patients they were expected to behave in the same way as in less seriously ill patients. Now the unpredictability of even the most reliable drugs has been recognized. ⋯ The drugs may not only interfere with the action of each other at the receptor and enzyme level, but may also change protein binding and elimination. All these effects may be unimportant in less seriously ill patients, but may affect outcome in the critically ill. A high degree of awareness and suspicion of unknown drug-induced adverse reaction is needed by clinicians and pharmacologists alike.
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1. Antipyrine (AP) and sulphadimidine (SDD) plasma elimination and metabolite formation were studied in dwarf goats before and after treatment with phenobarbital (PB), triacetyloleandomycin (TAO), and rifampicin (RIF). 2. PB treatment significantly increased AP plasma clearance in both male and female goats. ⋯ In male goats, RIF had no effect on plasma elimination of AP and SDD. With SDD, it decreased the urinary excretion of the unchanged drug and its N4-acetylated metabolite. 7. Induction/inhibition studies of drug metabolism in food-producing animal species are desirable to gain more insight into the regulation of enzymes involved in the metabolism of xenobiotics.
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Review Comparative Study
Interspecies scaling and comparisons in drug development and toxicokinetics.
1. Methods of interspecies extrapolation using physiological models and allometric scaling have been reviewed with their possible application to drug development, both for candidate drug selection and the interpretation of toxicokinetic data. 2. Physiological models offer a mechanistic approach to extrapolation from one species to another, examining individual components which interrelate to produce the characteristics of the whole system. ⋯ For routine drug development, however, allometric scaling is potentially more useful since it uses data which are routinely obtained and the calculations are relatively simple. 6. The problems of intraspecies scaling from high-dose data to low-dose predictions are discussed with respect to current models of dose levels. A new approach is proposed using a modified Hill equation based on drug exposure, which should allow for a more meaningful determination of the toxicity of a compound with different drug exposures.(ABSTRACT TRUNCATED AT 400 WORDS)