Pharmacokinetics enzyme induction/inhibition

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. 

Pharmacokinetic interaction the drugs interact remotely from the target site to alter plasma (and other tissue) concentrations so that the amount of the drug at the target site of clinical effect is altered, e.g. enzyme induction by rifampicin will reduce the plasma concentration of warfarin enzyme inhibition by ciprofloxacin will elevate the concentration of theophylline. 

Greb WH, Buscher G, Dierdorf HD, Koster FE, Wolf D, Mellows G. The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine. Acta Psychiatr Scand Suppl 1989 350 95-8. 

Two typical phase I dmg interaction clinical trial designs are shown in Figure 20.4. Pharmacokinetic profiles are found within each subject for each substrate with and without concomitant exposure to the study dmg. These designs are applicable to both enzyme induction and inhibition effects (Figure 20.4, upper half). The same study schematic can be used to study the effects of inhibitors or inducers on the study dmg as a substrate for CYP450 systems (as illustrated in the lower half of Figure 20.4). 

Multiple-dose pharmacokinetics to assess accumulation or changes in clearance caused by enzyme induction or inhibition... 

The pharmacokinetics and metabolism of phenazone (largely used as an investigational marker drug of enzyme induction or inhibition) were studied in two groups of patients with prostate cancer before and after they took either bicalutamide 50 mg daily (7 patients) or 150 mg daily (11 patients) for 12 weeks. Small changes in the phenazone pharmacokinetics were found (half-life reduced by 16.3% with the 50 mg bicalutamide dos-... 

From a clinical point of view, adverse drug interactions (therapeutically undesirable effects) are particularly important. These interactions reduce or enhance the effects of a drug, causing emergence of toxic symptoms or pharmacological action qualitatively different from that expected. Undesirable interactions require specific control of therapy or even modification of doses, and are a result of a variety of mechanisms and the impact of the patient s individual characteristics on drug metabolism. Sometimes completely unfamiliar or unusual mechanisms underlie two types of reactions, positive or adverse. Most often, however, these reactions are nothing other than repeated, sometimes very well-known, pharmacokinetic processes (pharmacokinetic interactions), most of which are a result of inhibition or induction of metabolic enzymes. 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

However, a retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interaction in patients who were also taking theophylline (127,128). Furthermore, in two doubleblind, placebo-controlled, randomized studies azithromycin did not inhibit the metabolism of theophylline (176,177). However, there has been a report of reduced theophylline concentrations after withdrawal of azithromycin (178). The authors concluded that the mechanism of interaction was best explained by concomitant induction and inhibition of theophylline metabolism by azithromycin, followed by increased availability of unbound enzyme sites as azithromycin was cleared from the system. 

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