Deep compartments

Although the lower limit of quantitation is established during assay validation and prior to microdosing, assay sensitivity remains an uncertainty until the actual analysis of the microdose samples as well. There is always the danger that plasma exposures from the microdose are lower than predicted and as a result plasma concentrations from some or all of the time points cannot be detected by the LC-MS/MS method. Reduction of this risk is achieved by collaborative communication between the bioanalytical chemist and the project team. Conservative estimates on bioavailability and clearance can be used to establish the necessary limit of detection needed to determine plasma concentrations for all time points. Updates on the progress of the assay development allow the team to decide if the achievable limit of detection will enable the determination of plasma concentrations from enough time points to make a go-no go decision. Of course, sensitivity is not an issue with AMS, which practically ensures that plasma concentrations will be determined, possibly for several days, enabling the observation of complex PK and clearance from deep compartments. 

However, in the light of multiple experimental findings based upon more accurate and precise techniques, this model seems to be oversimplified since it does not take into account the potential transfer of drugs from sweat, sebaceous and apocrine gland secretions, nor the external contamination even via deep compartments located in the skin surrounding the hair follicle. 

In OP-poisoned patients, Willems and coworkers found a volume of distribution for prali-doximeof2.77 1.451kg 1 in the 13-phase after 4.4 mg kg-1 IV followed by continuous infusion at 2.1 mgkg-1h-1 (Willems etal, 1992). In OP-poisoned patients treated with an obidoxime bolus 3.5 mg kg-1 IV followed by continuous infusion at 0.45 mgkg-1h the volume of distribution at steady state was 0.66 0.23 lkg-1 ( = 27 unpublished results). An even larger Vd of obidoxime, 0.85 lkg-1, was reported in a methamidophos-poisoned patient with renal failure (Bentur et al, 1993). These data point to a deep compartment that is filled only slowly. 

In a patient who had received obidoxime for 12 days and died 15 days after parathion poisoning, obidoxime concentrations in cartilage were 100-fold higher than in plasma (unpublished). These data indicate that the chondroitin sulfate-rich tissues may represent the deep compartment from which pyridinium aldoximes are slowly released. 

FIGURE 1.1 The three most commonly used pharmacokinetic models in explaining the pharmacokinetic behavior of drugs. The symbols C, P, S, and D represent central, peripheral, shallow, and deep compartments, whereas the first-order rate constants, symbolized by k j, represent drug transport from compartment i to compartment j. ka, and kd represent a bolus rV dose, the absorption rate constant, and constant rate infusion, respectively. 

The many factors that can alter Vss and/or Cl, and thereby shorten or prolong T1/2 are discussed in detail elsewhere. They include altered fluid balance, nutritional status, percentage of body fat, species, hormonal status, age of animal, and disease status. For example, renal and/or hepatic disease can reduce Cl and therefore prolong Ti/2 for the therapeutic phase, while infectious diseases may either increase or decrease Cl and/or Vss- In contrast, the main factor controlling the slope of the very late terminal phase is the redistribution of the drug from a deep compartment to plasma. 

The site of the pharmacological action of an active substance is not always known. In most cases the active substance can reach the site of action when it is injected subcutaneously or intramuscularly, or into the venous or arterial bloodstream. Sometimes it is necessary to inject the medicine directly into a deep compartment such as the central nervous system. Some active substances can only reach a specific compartment with a transport carrier. Some charged or large molecules can reach specific tissues incorporated in liposomes (see also Sect. 13.2.2). 

Percutaneous sclerotherapy usually is performed under general anesthesia and with fluoroscopic monitoring, using pure (96%) ethanol, Ethibloc, and water-iodinated contrast material. FD-CT provides valuable cross-sectional visuafization of deep compartments of facial venous malformations for better control and safety during embohzation (Fig. 40.14). 

Anisotropine methyIbromide shows a sustained excretion rate in man, possibly indicative of a "deep" compartment and is orally absorbed 2. 

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