Two-compartment open model

Fig. 39.1. Two-compartment open model composed of a central (plasma) compartment and a target (skin) compartment. This model assumes that a dmg is delivered rapidly into plasma from which it is either exchanging with the target organ or eliminated by excretion or metabolism.

No modern studies of the human pharmacokinetics of LSD have been done, largely because human experimentation has virtually stopped. An older study that used a spectrofluorometric technique for measuring plasma concentrations of LSD was done in humans given doses of 2 Mg/kg i.v. After equilibration had occurred in about 30 min, the plasma level was between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a small amount of LSD was present after 8 hr. The half-life of the drug in humans was calculated to be 175 min (2). Subsequent pharmacokinetic analysis of these data indicated that plasma concentrations of LSD were explained by a two-compartment open model. Performance scores were highly correlated with concentration in the tissue (outer) compartment, which was calculated at 11.5% of body weight. The new estimation of half-life for loss of LSD from plasma, based on this model, was 103 min (47). 

Pharmacokinetics The absorption rate of Gonal-F following subcutaneous or intramuscular administration was found to be slower than the elimination rate. Hence the pharmacokinetics of Gonal-F are absorption rate-limited. After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two-compartment open model with a distribution half-life of about 2 to 2.5 hours. Steady-state serum levels were reached after 4 to 5 days of daily administration. 

Plasma protein binding of LSD is >80%. As the drug penetrates the CNS, it is concentrated in the visual brain areas and the limbic and reticular activating systems, correlating with perceived effects. LSD is also found in the liver, spleen, and lungs.5 The volume of distribution is reported to be low at 0.28 L/kg.1 Wagner et al.6 described a two-compartment open model for LSD with an elimination half-life of 3 h. 

A.2 Two-Compartment Open Model When the dmg concentration -time profile demonstrates a biexponential decline following IV dosing, a two-compartment model that is the sum of two first-order processes (distribution and elimination) best describe the data (Fig. 2.4). A dmg that follows the PK of a... 

Fig. 7.1 Two-compartment open model with plasma and tissue elimination.

In swine, following intra-aortic administration, the disappearance of parent T-2 toxin followed a two compartment open model with mean elimination phase half-life of 13.8 min and mean apparent specific volume of distribution of0.3661/kg (Beasley et al, 1986). Parent T-2 toxin was not detected in plasma, urine, or liver but was transiently present in lymphoid tissues. T-2 toxin and metabolites were eliminated as glucuronide conjugates into bde, undergoing deconjugation in the intestinal tract by microbial action and then underwent enterohepatic recirculation (Corley et al, 1985). 

Figure 3 (a) Schematic representation of a two-compartment open model i.v., intravenous administration, V-, and I4, respective volumes of compartments 1 and 2 icai and fci2. transfer rate constants between compartments 1 and 2 ke, elimination rate constant, (b) Time course of blood concentration following intravenous administration A and B, proportionality constants a and p, elimination rate constants corresponding to each segment of the curve. 

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]. 

Pharmacokinetic analysis indicated that a two-compartment open model best characterized the disposition of 2,4-DNP in the serum, liver, and kidney of mice given a gavage dose of 22.5 mg/kg of 2,4-DNP (Robert and Hagardorn 1983). Serum and tissue levels of parent compound were quantitated by a highly specific capillary GC-MS method at 1-24 hours postdosing. Half-times for the slow terminal elimination phases were 7.7 hours for serum, 8.7 hours for liver, and 76.2 hours for kidney. The authors suggested that the apparent persistence of 2,4-DNP in the kidney could be related to tissue binding of the compound. 

Pharmacokinetic analysis indicated that two-compartment open models best characterized the disposition of 2,4-DNP and 2-amino- 4-nitrophenol from plasma, whereas a three-compartment open model best characterized the disposition of 4-amino-2-nitrophenol from plasma. The elimination half-lives (tV2) for the terminal phase were estimated at 10.3 hours for 2,4-DNP, 46.2 hours for 2-amino-4-nitrophenol, and 25.7 hours for 4-amino-2-nitrophenol. 

Gibaldi M. Estimation of the pharmacokinetic parameters of the two-compartment open model from post-infusion plasma concentration data. J Pharm Sci 1969 58 1133-1135. 

The elimination kinetics of diazepam in humans has been described by a two-compartment open model, with a plasma clearance of 26-35 ml min-1 after a single intravenous dose (Klotz et al., 1975 Andreasen et al., 1976 Klotz et al.,... 

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. ...

FIGURE 13.1 Classical pharmacokinetic modeling of a two-compartment open model. The symbols C and P represent the central and peripheral compartments, whereas K represents the first-order transfer constants between compartments. The subscripts, a and e, represent absorption and elimination, whereas 12 and 21 represent transfer of drug between compartments 1 and 2 (central to peripheral) or 2 and 1 (peripheral to central). 

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