Three-compartment model

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

The vesicant vinorelbine is structurally similar to vincristine and may cause many of the same side effects as vincristine. While this vesicant is administered intravenously over 6 to 10 minutes, patients should be counseled about neuropathy, ileus, and myelosuppression. The pharmacokinetics of vinorelbine are best described by a three-compartment model, with an a half-life of 2 to 6 minutes, a 3 half-life of 1.9 hours, and a y half-life of 40 hours. Vinorelbine has shown efficacy in the treatment of breast cancer and non-small cell lung cancer. Additional side effects include myelosuppression, paresthesias, and mild nausea and vomiting. 

Docetaxel, another taxane, binds to tubulin to promote microtubule assembly. The pharmacokinetics of docetaxel are best described by a three-compartment model, with an a half-life of 0.08 hours, a 3 half-life of 1.6 to 1.8 hours, and a terminal half-life of 65 to 73 hours.14 Docetaxel has activity in the treatment of breast, non-small cell lung, prostate, bladder, esophageal, stomach, ovary, and head and neck cancers. Dexamethasone, 8 mg twice daily for 3 days starting the day before treatment, is used to prevent the fluid retention syndrome associated with docetaxel and possible hypersensitivity reactions. The fluid... 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Epirubicin inhibits both DNA and RNA polymerases and thus inhibits nucleic acid synthesis and topoisomerase II enzymes. Epirubicin pharmacokinetics are best described by a three-compartment model, with an a half-life of 4 to 5 minutes, a... 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

Leggett (1992) also proposed a respiratory tract model. Deposition of americium particles, depending on their size, are assumed to deposit in three compartments representing extrathoracic, fast-clearing thoracic, and slow-clearing thoracic regions of the respiratory tract (Figure 3-8). 

Fig. 7 A three-compartment pharmacokinetic model describing targeted drug delivery. (From Ref. 46.)...

Figure 7.20 Three-compartment equilibrium distribution model (after Kubinyi [23]).

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

The three-compartment tissue model is ordinarily simplified by lumping all three subcompartments, lumping subcompartments 1 and 2, or lumping subcompartments 2 and 3. These simplifications result in the blood flow-limited (i.e., lumping all three subcompartments) and the membrane-limited (i.e., lumping any two subcompartments) tissue models. Differential mass balance equations for a noneliminating membrane-limited compartment are... 

The Leggett Model simulates lead biokinetics in liver with two compartments the first simulates rapid uptake of lead from plasma and a relatively short removal half-life (days) for transfers to plasma and to the small intestine by biliary secretion a second compartment simulates a more gradual transfer to plasma of approximately 10% of lead uptake in liver. Different transfer rates associated with each compartment are calibrated to reproduce patterns of uptake and retention of lead observed in humans, baboons, and beagles following intravenous injection, as well as blood-to-liver concentration ratios from data on chronically exposed humans. Similarly, the Leggett Model simulates lead biokinetics in three compartments of soft tissues, representing rapid, intermediate, and slow turnover rates (without specific physiologic correlates). 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Figure 1 A schematic conceptualization of the three-compartment model of CNS penetration demonstrating the importance of intercompartmental unbound compound concentration relationships to target pharmacology interactions [21,22,25-28]. An exaggerated synapse is shown in the brain compartment to emphasize the locale of transmembrane proteins (squares) versus intracellular (oval) targets, and the matrix compound concentrations dictating their respective ligand-target interactions.

To calculate these measures in PET/SPECT, typically two- or three-compartment models are employed. Such models have been the basis for extension into neuroreceptor imaging of the methods described below. 

Here T is the uniform temperature in the CV. Equations (3.45) and (3.48) are all equivalent under the three approximations, and either could be useful in problems. The development of governing equations for the zone model in compartment fires is based on these approximations. The properties of the smoke layer in a compartment have been described by selecting a control volume around the smoke. The control volume surface at the bottom of the smoke layer moves with the velocity of the fluid there. This is illustrated in Figure 3.10. 

Models may contain any number of compartments but single-compartment models are generally inaccurate for studying pharmacokinetics. A three-compartment model allows fairly accurate modelling with only limited complexity. 

Gale, R.W. 1998, Three-compartment model for contaminant accumulation by semipermeable membrane devices. Environ. Sci. Technol. 32 2292-2300. 

Another experimental animal model for exploring the reinforcing effects of drugs of abuse is the conditioned place preference (CPP) procedure. A distinctive environment (e.g., one compartment of a two- or three-compartment apparatus) is paired repeatedly with administration of a drug, and a different environment is repeatedly associated with administration of vehicle. CPP occurs when repeated administration of a drug in this particular environment results in the ability of that environment to elicit approach behavior and increased time contact (place preference) in the... 

Schizophrenia designates a group of mental disorders rather than a uniform disease. Eugen Bleuler (1911), who coined the term schizophrenia, disputed the then current Kraepelinian concept of dementia praecox because he had recognized that the disorders in question could have very different courses and outcomes. Specifically, not all patients with schizophrenic psychoses ended up in dementia praecox, i.e. with a premature loss of their mind. Carpenter and Buchanan (1994) suggested that the clinical manifestations of schizophrenia could be grouped into three relatively separate core domains of psychopathology (the three-compartment model of schizophrenia) ... 

A three-compartment model has been described for the toxicokinetics of A-nitroso-diethanolamine studied in CD-COBS rats after a low intravenous dose (5 mg/kg bw). Blood levels of A-nitrosodiethanolamine reflected the levels in the liver, suggesting that the liver may not accumulate A-nitrosodiethanolamine. The overall elimination rate corresponded to a half-life of 5.77 h (Airoldi et al., 1984a). 

The models consist of interconnected compartments, with the drug moving between them at rates proportional to the concentration gradient, i.e. a first order process. A model with only one compartment describes the behaviour of few substances, e.g. indocyanine green and possibly warfarin, that are almost totally confined to the circulation and do not diffuse into the tissues. For most drugs, two or three compartments are required to adequately describe their disposition. 

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