Induction pharmacokinetic effects

Variations of the biological activity are not necessarily linked to the induction of effects at the level of a given receptor, but could have come from a pharmacokinetic factor (urinary or biliary excretion, plasma protein binding, differential metabolism). A case of differential metabolism is illustrated by the comparison of the toxicities of odd and even u>fluoro acids. " The (3-oxidation of odd chain length compounds leads to the extremely toxic fluoroacetic acid, while that of the acids with even numbers of carbon atoms generates 3-fluoropropionic acid which is clearly less toxic (Table 14.3). 

In the biological domain, variations of activity are not necessarily linked to the induction of effects at the level of a given receptor, but could have come from a pharmacokinetic factor (urinary or biliary excretion, plasma protein... 

Aprepitant inhibits the cytochrome P450 isoenzyme CYP3A4 by which midazolam is metabolised, resulting in increased midazolam levels. The pharmacokinetic effect on intravenous midazolam indicate the effects of aprepitant on systemic rather than on intestinal CYP3A4 activity. Aprepitant is also a mild inducer of CYP3A4, however the induction is transient, with maximal effect 3 to 5 days after the end of treatment. 

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

The biological effects observed at tumour sites indicate that BsMAbs effectively penetrate tissue. However, trials are limited by the toxicity caused by induction of a cytokine storm or by the complex pharmacokinetics. Furthermore, T-cell directed BsMAb approaches are hindered by difficulties in mobilizing and activating T and NK effector cells. Recent attention, therefore, has focused on BsMAbs which target myeloid effectors [79]. 

The study of absorption, distribution, metabolism and excretion in toxicology studies, usually referred to as toxicokinetics, provides extremely useful information on the pharmacokinetics of high doses and of repeated doses of the compound. The dose dependency of the pharmacokinetics and the possible time effects, e.g. a decrease in exposure over time as a result of enzyme induction, is essential information for the interpretation of the toxicity findings as well as for the planned clinical studies. 

Pharmacokinetics. Seed oil, administered intramuscularly to dogs at a dose of 1 mL/kg labeled glyceryl trioleate injected with the oil, was distributed primarily to iliac nodes, heart, liver, and lungs 5 Phytotoxic effect. Ethanol (95%) extract of the dried seed oil, at a concentration of 500 ppm, was inactive. The biological activity reported has been patented " k Prostaglandin induction. Seed oil, administered subcutaneously to rats at a dose of 1 g/day for 14 days, stimulated PGl-2 synthesis in the thoracic aorta . ... 

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

Putnam W, Desai DG, Hung Y, Woo JM, Benet LZ. The effect of induction conditions and MDR1 genotypes on dicloxacillin pharmacokinetics [abstr]. Clin Pharm Ther 2003 73 57. 

Nutritional status determines effects of therapeutic drugs and recognition of these factors should lead to improved drug therapy. Pharmacokinetics are changed by a person s diet but metabolic tissue and cellular effects are not well understood. Biochemical transformations and enzyme inductions that decrease or increase toxicity of drugs are discussed and numerous examples given. 

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