Enzyme proteins, pharmacodynamic

Sometimes it is not possible to measure the direct effect of the drug. Endpoints or surrogate biomarkers are used to monitor the pharmacodynamics and pharmacokinetics of the drug. These markers may be changes in blood pressure, cholesterol level, concentrations of certain enzymes, proteins, blood glucose levels, and similar factors (see Table 6.2 for serum tumor markers and Appendix 7 for general biomarkers). 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

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 term pharmacodynamics encompasses all the processes that influence the relationship between drug concentration and resulting effects. Psychotropic drugs have a wide variety of targets within neuro transmitter systems, including neurotransmitter synthesis, degradation of enzymes, storage, receptors, and specific transporter proteins. 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

If volunteers are required to give specimens for genotyping for drug metabolising enzymes or for proteins that might be involved in pharmacodynamic responses, a separate consent form should be provided for this purpose. If it is intended that a DNA sample be stored for future analysis, consent should be requested and it should be made clear that all data will be held in a format which will make it impossible to link the data to an identifiable individual. Subjects should be free to refuse or withdraw consent independent of their consent to participation in the study. In the event of a withdrawal, any samples taken should be destroyed. 

Among the remainder, four of the five proteins are variants on interleukins, with the fifth (Beromun ) being a recombinant shortened version of tumor necrosis factor-alpha (TNF-alpha). Only one enzyme is hsted this is a pegylated version of an old treatment, where asparaginase (see Part II, Chapter 6) has been coupled to polyethylene glycol for better pharmacodynamics. The remainder of the 18 are composed of three recombinant interferons, including two of the earliest. 

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