Two-compartment intravenous injection

Fig. 39.12. (a) Two-compartment mammillary model for single intravenous injection of a doseD. The buffer compartment exchanges with plasma with transfer constants and k p. (b) Time courses of the... 

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). 

Figure 30.6 shows a prediction of the plasma concentration of ARA-C and total radioactivity (ARA-C plus ARA-U) following administration of two separate bolus intravenous injections of 1.2 mg/kg to a 70-kg woman. All compartment sizes and blood flow rates were estimated a -priori, and all enzyme kinetic parameters were determined from published in vitro studies. None of the parameters was selected specifically for this patient only the dose per body weight was used in the simulation. The prediction has the correct general shape and magnitude. It can be made quantitative by relatively minor changes in model parameters with no requirement to adjust the parameters describing metabolism. 

Hypotension follows the intravenous injection of benzodiazepines, but is usually mild and transient (SED-11, 92) (56), except in neonates who are particularly sensitive to this effect (57). Local reactions to injected diazepam are quite common and can progress to compartment syndrome (SEDA-17, 44). In one study (58), two-thirds of the patients had some problem, and most eventually progressed to thrombophlebitis. Flunitrazepam is similar to diazepam in this regard... 

After intravenous injection of 0.4mg/kg in healthy volunteers, plasma acarbose concentrations declined biexponentially and fitted the equation for an open two-compartment model. The volume of distribution of acarbose at steady state following intravenous administration was calculated to be about 0.321/kg while the apparent volume of the central compartment was 0.161/kg. The mean distribution half-life was found to be approximately 0.5 h after intravenous injection (Putter et al.. 1982) and 3.7 h following oral administration (Muller and Hillebrand, 1986). 

The pharmacokinetics of thalidasine in a polyphase liposome preparation and in aqueous solution were determined by HPLC in mice following intravenous injection. The blood drug concentration curve fit a two-compartment open model, with the distribution and elimination half-lives being 3.52 and 23.58 minutes, respectively, for the liposome preparation, and 1.293 and 11.12 minutes, respectively, for the aqueous solution [149]. 

After an intravenous bolus dose, serum concentrations decrease as if the drug were being injected into a central compartment that not only metabolizes and eliminates drug but also distributes drug to one or more other compartments. Of these multicompartment models, the two-compartment model is encountered most commonly (see Fig. 5-5). After an intravenous bolus injection, serum concentrations decrease in two distinct phases described by the equation ... 

Following intravenous injection, Tc-HSA is distributed homogenously in the vascular compartment. It does not concentrate in the thyroid, salivary, and gastric glands. In pregnant women receiving a placental scan, 50-75% of the radioactivity was measured in the blood 30 min after injection. The ehmination from blood has been described by two half-times, namely 6 h and 3 days (McAfee et al. 1964 Stern et al. 1966). 

Pharmacokinetic evaluations of hypericin 1 and pseudohypericin 2 in experimental animals are restricted to studies in mice. Following intravenous injection of 17.5 mg/kg of synthetically prepared hypericin peak concentrations of 27.8 pg/ml were measured at 10 min and decreasing values could be followed for a period of 240 h (10 ng/ml). The data were well adjusted to a two-compartment model with a distribution phase (ti/2a) of 2 h and an elimination half life (ti/2(3) of 38.5 h. The volume of... 

Onkelinx et al. (1973) analyzed the kinetics of Ni(II) in rats and rabbits by use of a two-compartment mathematical model. These authors generated computer-fitted curves to depict the distribution of Ni(II) in extracellular and tissue spaces, as well as the excretory clearances of " Ni in urine and feces. This model was consistent with the observed distribution of nickel in tissues of nickel-treated rats and rabbits in various experiments, as summarized by Sunderman (1986b). In rabbits killed 2 h after an intravenous injection of " Ni(II), the relative uptake of " Ni in various tissues was ranked as follows kidney > pituitary > skin > lung... 

Two-compartment models are frequently used when the disappearance of an intravenously injected agent follows a bi-exponential decay. The parameters Ai, A2, a, and are estimated from the data, using methods described elsewhere [2]. With the two-compartment model, ehmination from the central compartment occurs in two phases a fast phase with half-life ti/2-a = ln(2)/a, which is often attributed to drug distribution from the central compartment (compartment 1) to the peripheral compartment (compartment 2), and a slower phase with half-life = ln(2)/ 8, which is usually attributed to drug elimination from the central compartment. Since the initial concentration within the central compartment is known, c , it must be equal to the sum of the two constants, A + A2 (obtained from Equation 7-12 when t = 0). These constants, AI and. <42, indicate the fraction of the initial dose that is eliminated from the central compartment during the fast and slow phases, respectively (see example below for antibody kinetics). These parameters can be related to the transfer and elimination constants in the original model ... 

In healthy human subjects, a peak mean scrum concentration of 1607 p.g/liter was found 15 min after single bolus intravenous injections of 20 mg (Hilleslad etal.. 1974). A two-compartment open model has been used to describe elimination kinetics of diazepam in humans after single intravenous injections were reported (Andreasen etal., 1976 Klotz etal., 1975, 1976). A two-compartment open model has also been used to describe elimination kinetics of diazepam in experimental animals however, there were major interspccics differences in parameters such as r / and (Klotz etal., 1976), which indicated caution in the interpretation of animal studies. In human volunteers, the plasma protein binding of diazepam was greater than 95% (Klotz etal., 1976). The f /j of diazepam appears... 

Fig. 9.28. Semilogarithmic plot of drug concentration in the plasma against time following administration of a rapid intravenous injection when the body may be represented as a two compartment open model. The dashed line is obtained by feathering the curve. ...

Following the administration of a drug by an intravenous injection, if it is necessary to use a two-compartment model, the area under the plasma concentration-time curve from f = 0 to f = f (the last sampling time) may be estimated by using trapezoidal rules, as mentioned earlier. Additionally, the area under plasma concentration-time curve from f = f to f = may be computed using the following equation ... 

Thus, in the simple case of an open two-compartmental system depicted in Figure 9 which is composed of two mutually interconnected compartments— the central one into which the drug is injected and the peripheral —the decline of drug concentration in plasma forming part of the central compartment is after a rapid instantaneous intravenous injection given by ... 

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