Measurements drug levels

Many tests for therapeutic drugs require careful timing between administration and sample collection if the measured drug level is to be of optimal use clmically. Therapeutic and toxic intervals for which definitive liinits do not exist have been omitted from tlie table.-Drugs are listed by their chemical or generic name, followed by a commercial brand of the drug (where appropriate). 

In addition to intravenous studies, estimates of the oral bioavailability of the drug need to be provided. For glucocorticoid studies, often very large doses of steroid have to be given to be able to obtain measurable drug levels. The percent oral bioavailability can then easily be obtained by comparing the dose-adjusted area under the concentration-time profiles after oral and IV administration ... 

If the delay between measured drug levels and response is very long, additional effect compartments can be added to allow the model to describe a longer lag period. A schematic diagram of an indirect effect model with the additional effect compartment for a precursor added is provided in Figure 41.3. 

Another important aspect is the correlation of pharmacokinetic (PK) and pharmacodynamic (PD) data, which is subject of PK/PD-modeling. In ideal settings, tools are available to measure drug levels and effects, and most ideally mathematic models can be derived to describe the relationship of both parameters. 

If the organ systems that determine the rate at which the drug leaves the body are changing, then it is advisable to measure drug levels to maintain the drug at optimal levels. 

The main interest of in vivo NMR is obvious. Measuring drug levels in plasma does not always reflect the drug concentration at the receptor sites, which are generally located in the tissue cells of the target organ. Consequently, a method that allows one to measure the concentration of drugs and their metabolites in situ may be extremely useful. 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

First described in 1926 by Perrin [16], the theory was greatly expanded by Weber [17], who developed the first instrumentation for the measurement of FP. Dandliker [18] expanded FP into biological systems such as antigen-antibody reactions and hormone-receptor interactions. Jolley [19] developed FP into a commercial system for monitoring of therapeutic drug levels and the detection of drugs of abuse in human body fluids. 

S. 0ie and J.-D. Huang, Binding, should free drug levels be measured in Topics in Pharmaceutical Sciences 1983 (D. D. Breimer and P. Speiser, Eds.), Elsevier, Amsterdam, 1983, pp. 51-62. 

Plasma and urine levels of the drug are determined by chromatographing the trimethyl-silyl derivative of dobutamine on a 6-foot column packed with 3.0% UC-W98 silicon gum rubber (methyl-vinyl) on Diatoport S operated at 260°C. The hydrogen flame detector is maintained at 280°C. Helium flow rate is 60 ml/min. The retention time of dobutamine derivative (TMS) under these conditions is 3.8 minutes. This method measures plasma levels as low as 1 ig/ml (4). 

Lehane, D.P. et al. 1976. Therapeutic drug monitoring Measurements of antiepileptic and barbiturate drug levels in blood by gas chromatography with nitrogen-selective detector. Ann Clin Lab Sci. 6 404. 

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

Drug Levels in Plasma. Drug levels may also be measured in a clinical trial. Such levels are usually part of a pharmacokinetic analysis but also provide important safety data. This information would be particularly relevant in cases of suspected or actual drug overdosage, drug interactions, to correlate medicine levels with toxic events, or in other situations. It must be clarified whether free levels of the drug and/or the protein bound will be measured by the laboratory. 

Absorption evaluation from luminal disappearance of drugs has been widely employed as a simple and easy method. Although the appearance of drugs in the mesenteric blood can provide a more sensitive way that enables to detect lower levels of absorption, it is technically more complicated, especially due to the colon s anatomical and morphological configuration. Another alternative for absorption evaluation is to measure drugs that appear in the systemic circulation, although this method cannot provide a direct measure of membrane permeability. 

Consideration will be given mainly to the principles of pharmacokinetics and methods of measuring drugs whose effectiveness derive from their ability to alter the patient s own metabolism, either locally or generally, and for which there is reasonable evidence that therapeutic responsiveness and/or toxicity is related to the steady-state blood drug level. 

These examples are given to show that a simplistic approach to therapy, which is based upon clinically useful but unproved hypotheses of disease causation, can lead to the neglect of studies into the relationship between blood drug levels and clinical response, as determined by morbidity and mortality, rather than by some easily measured but possibly irrelevant chemical parameter. 

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