Pharmacokinetics induction/inhibition

For the sake of simplicity, simple monophasic pharmacokinetics (one compartment and one half-life) was assumed in the above example and in many other examples in this report. In real life, most chemicals express biphasic or polyphasic pharmacokinetics (several compartments and several half-lives). Squeezing a polyphasic pharmacokinetic behavior into a one-compartment model by assuming a single half-life may lead to negligible errors for some chemicals and serious misinterpretation of biomarker concentrations for others. The same can be said about nonlinear processes, such as metabolic induction, inhibition, and saturation. A good way to check the accuracy of a simple pharmacokinetic model is to verify its performance by comparing with a physiologically based pharmacokinetic (PBPK) model that may encompass the mentioned factors. 

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. 

Toxicity is a major cause for the withdrawal of drugs from the market and it is a major concern for pharmaceutical researchers. Reactive metabolism is certainly a very hot topic within the whole approach to drug metabolism. The downstream consequences of not identifying reactive metabolites may be financially catastrophic. There is an increasing drive to have early prediction of the metabolic fate and interactions of candidate drug molecules. Factors such as metabolic stability, toxic metabolite production, and P450 inhibition and induction are all routinely monitored to prevent compounds with poor pharmacokinetic properties from progressing forward onto clinical trials. 

Lin JH, Lu AYH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 1998 35 361-390. 

Pharmacologically based pharmacokinetic (PBPK) models have also been incorporated into the assessment of responses to mixtures of some substances where interactions may occur. This was suggested for application in assessing human health risks of contaminants in drinking water (Krishnan et al. 1997) on the basis that most interactions between organic substances occur as a result of induction or inhibition of metabolism. This has been applied in predicting the maximal likely interaction in mixtures of chlorinated and nonchlorinated hydrocarbons (Haddad et al. 2000) and aromatic petroleum hydrocarbons (Haddad et al. 1999). Metabolic and other data are required for PBPK models, and, as these may only be available for a few organisms in the environment, they are not yet widely used for extrapolation. 

The time at steady state before collection of endpoint or pharmacokinetic observations depends on whether inhibition or induction is to be studied. Inducers can take several days or longer to exert their effects, while inhibitors generally exert their effects more rapidly. Thus if induction is to be assessed, a more extended profiling period after attainment of steady state for the substrate and interacting drag may be necessary... 

In a study of the effects of itraconazole 200 mg/day and rifampicin 600 mg/day on the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg during and 4 days after the end of the treatment, switching from inhibition to induction of metabolism caused an up to 400-fold change in the AUC of oral midazolam (54). 

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. 

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. 

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. 

Pharmacokinetics and absorption of the drug should be linear. If the pharmacokinetic processes are dependent on the fraction of dose reaching the systemic blood flow (or of the dose administered) or on the rate of absorption, comparison between formulation and simulation cannot be made. This non-linearity may be owing to saturable absorption processes (active absorption), induction or inhibition of the metabolism, the first past effect, which is rate/absorption dependent, etc. Those points must be studied before any attempt to establish an IVIVC. 

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