Intravenous injection kinetics

FIGURE 5.40 Schematic representation of the concentration of a chemical in the plasma as a function of time after an intravenous injection if the body acts as a one-compartment system and elimination of the chemical obeys first-order kinetics with a rate constant... 

Comparison of the kinetic features of different LMWPs revealed that all LMWPs tested so far (such as lysozyme, cytochrome-c and aprotinin) are quickly cleared from the circulation and accumulate rapidly in the kidney [38]. The fractions of the injected LMWP that are reported to be taken up by the kidney vary between 40-80 % of the injected dose. In our studies, using external counting of radioactivity, at least 80 % of the intravenously injected LMWPs was finally taken up by the kidneys, which is in agreement with renal extraction studies [69,70]. However, studies in which the actual amount of LMWP in the kidney was measured directly in the tissue, indicated a lower, but still substantial accumulation of 40% of the injected dose [71,72]. Apart from the kidney, LMWPs do not seem to accumulate elsewhere in the body (Figure 5.8). 

The delay is probably due to the late absorption of the isopeptide (in the distal part of the small intestine) while free lysine is absorbed in the duodenum. After its late absorption, the isopeptide is transported readily to the kidneys which hydrolyze it very rapidly (as indicated by the kinetics of the expiration of 14C02 after intravenous injection) (see Figure 4). Since no free isopeptide was found in the urines, this hydrolysis is complete. 

Toxico-kinetic studies showed, that the adsorption of iron blue pigments is very low. Following intravenous injection of a Fe radio-labeled iron blue pigment, the Fe(CN)6- ion was rapidly and virtually completely excreted with the urine. After oral administration of ferric hexacyanoferrate ( Fe) approx. 2% of the labeled hexacyano-ferrate ion was adsorbed by the gastro-intestinal tract [3.199]. Most of the substance is excreted with the feces [3.200] and there was no evidence of its decomposition. 

Sontag (1986) Pharmacokinetic Model. An extended multicompartmental model (see Figure 2-9) describing the kinetic behavior of uranium (absorption, distribution, and excretion as a function of time) in the organs of male and female rats was developed using data taken from experiments performed on 13-month-old male and female Sprague-Dawley rats intravenously injected with 1.54 mCi/kg (57 kBq/kg) U-uranyl citrate and sacrificed at 7, 28, 84, 168, or 336 days after injection. 

FIGURE 4.4 Kinetic analysis of plasma concentrations resulting from the intravenous injection of NAPA- C ( ) and the simultaneous oral administration of a NAPA tablet (A). The solid lines are a least-squares fit of the measured concentrations showm by the data points. The calculated percentage of the oral dose remaining in the gastrointestinal (GI) tract is plotted in the insert. (Reproduced lAuth permission from Atkinson AJ, Jr. et al. Clin Pharmacol Ther 1989 46 182-9.)... 

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. 

Table 7.1 Disposition kinetics of enrofloxacin and formation of ciprofloxcin in newborn and one-week-old Finnish Ayrshire calves. A single dose (2.5 mg/kg) of enrofloxacin was administered by intravenous injection to the calves (n = 4 in each age group). Results are expressed as mean + SEM and (range).

In earlier studies In which macromolecules were released from polymers In vivo (11). the substances tested were proteins or DNA which were metabolized. Thus, a direct comparison of vivo and vitro release was Impossible. We therefore chose the polysaccharide Inulln which has a molecular weight of 5200 daltons. Inulln was chosen as a marker because It Is not metabolized, not excreted by the glomerulus, and Is neither reabsorbed or secreted by the kidney tubules. It Is not bound by plasma proteins and Is not toxic (1. Complete recovery of 3h-inulln (14) or cl -lnulin (15) in urine has been observed from Intravenous Injection Into rats, rabbits, dogs and humans. Thus, Inulln provides an excellent marker for comparing In vitro and In vivo release kinetics because Inulln recovered In urine can be directly compared to Inulln collected In vitro. 

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... 

Figure 10.2-7. MicroPET imaging to visualize the kinetics of gene expression in mice. Mice were transduced with either a D2R PET or a HSVl-sr39TK PET reporter gene by intravenous injection of adDTm. Reprinted from Ref. 22, with permission from Elsevier. (This figure is available in fnll color at ftp //ftp.wiley.com/public/sci tech med/ pharmaceutical biotech/.)...

It is precisely the formation of protein-bound DNIC that was responsible for long-term hypotensive effects of low-molecular DNIC with thiol-containing ligands after their intravenous injection to rats [52,82,83]. Most probably, the sharp decrease of the total peripheral resistance (TPR) as a specific response to DNIC treatment was a natural manifestation of vasodilator activity of DNIC. After cessation of hypotension, arterial pressure (AP) and TPR dropped down to the initial level [52]. The characteristic changes in AP caused by intravenous injection in experimental rats with DNIC-cys (1 20) (2.74 pmol/kg) and the kinetics of disappearance of protein-bound DNIC from circulating blood are shown in Figure 7.8. 

Only a few kinetic studies on Apo C have been realized in vivo in humans [17, 18, 20-23]. Recently, intravenous injection of iodine-labeled Apo C-I, C-II, and C-III, free or associated to HDL, has allowed to quantification of the metabohsm of each apoprotein in healthy volunteers. 

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