Linear Two-compartment Open Model Research Articles

Determination of morphine by high-performance liquid chromatography with electrochemical detection: application to human and rabbit pharmacokinetic studies

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with coulometric electrochemical detection was developed for the determination of morphine in human, rabbit, pig and dog plasma. It includes a one-step extraction procedure with hexane–isoamyl alcohol (1:1, v/v) at pH 8.9 (adjusted with phosphoric acid) and reversed-phase liquid chromatography on a μPorasil column. The mobile phase was composed of 5 m M sodium acetate buffer (pH 3.75)–acetonitrile (25:75, v/v). A flow-rate of 1.2 ml/min at 20°C was used. The working potentials for the electrochemical detector were +0.20 V for detector cell 1, +0.55 V for detector cell 2 and +0.75 V for the guard cell. The limit of detection of morphine was 100 pg/ml of plasma. Repeatability, precision and accuracy were also determined concomitantly. The calibration graphs were linear in the concentration range 0.25–250 ng/ml with correlation coefficients of 0.998±0.01 and with a minimum intercept of 0.05±0.08. The precision in plasma was acceptable, with coefficients of variation less than 11%. The absolute recoveries of morphine and nalbuphine (internal standard) were between 86 and 89% and independent of morphine concentration. Pharmacokinetics after oral morphine [MST Continus™ (morphine sulphate tablets) 30 mg, Bard Pharmaceutical, Cambridge, UK] in humans revealed a one-compartment first-order absorption model with one absorption phase and one elimination phase. The absorption and elimination half-lives were 2.46 and 1.80 h, respectively. Pharmacokinetics after intravenous morphine (3 mg/kg) in rabbits showed a linear two-compartment open model with one distribution phase and one elimination phase. The distribution and elimination half-lives were 0.5 and 33.8 h, respectively.

The effect of aging on the pharmacokinetics of nalbuphine in rabbits

For the purpose of selecting an animal model for the study of the aging effect on the pharmacokinetics of nalbuphine, the pharmacokinetic properties in young and in aged rabbits were reported. Thirty-one healthy New Zealand white rabbits ranging in ages (mean) from three months to 43 months (six three months old, group I; nine eight months old, group II; nine 18 months old, group III; and seven 43 months old, group IV) were included in the study. After intravenous bolus injection of nalbuphine (10 mg kg-1) to each rabbit, plasma samples were collected and analysed for nalbuphine by a high-performance liquid chromatography method. The plasma concentration-time data regarding nalbuphine were successfully fitted to a linear two-compartment open model. The elimination half-life of nalbuphine in rabbits increased significantly with age. Consequently, clearance decreased significantly with age. The parameter AUCO-affinity, which is derived from dose/clearance, increased significantly with age. The effect of aging on the pharmacokinetics of nalbuphine in rabbits is quite similar to that in humans. From the present study, it is concluded that rabbits may be suitable for the study of aging effects on the pharmacokinetics of nalbuphine.

Pharmacokinetic Parameters in CNS Gd-DTPA Enhanced MR Imaging

Dynamic MR imaging can be used to study tissue perfusion and vascular permeability. In the present article a procedure for dynamic MR is presented, which (a) accurately resolves the fast kinetics of tissue response during and after intravenous infusion of the paramagnetic contrast medium Gd-DTPA and (b) yields a linear relationship between the measured MR signal and the Gd-DTPA concentration in the tissue. According to these features, the measured signal-time curves can be analyzed within the framework of pharmacokinetic modeling. Tissue response has been parameterized using a linear two-compartment open model, with only negligible effects of the peripheral compartment on the central compartment. The three model parameters were fitted to the signal-time data pixel by pixel, based on a set of 64 rapid SE images (SE 100/10 ms, image scan time 13 s, interscan intervals 11 s). This makes it possible to construct parameter images, whereby structures become visible that cannot be distinguished in conventional Gd-DTPA enhanced MR. As a clinical example, the approach is discussed in a case of glioblastoma.

PHARMACOKINETICS OF ALFENTANIL IN TOTAL I. V. ANAESTHESIA

Alfentanil was administered, together with midazolam, as part of a total i.v. anaesthetic technique. The pharmacokinetics of alfentanil were determined in 10 female patients undergoing lower abdominal surgery. The dose regimen of alfentanil, based on simulation studies, consisted of a two-stage infusion following an initial bolus dose. The kinetics of alfentanil were described by a linear two-compartment open model. The total plasma clearance ranged between 93 and 431 ml min-1 (mean 249 ml min-1). The apparent volume of distribution at steady-state ranged between 0.27 and 0.64 litre kg-1 (mean 0.44 litre kg-1). The apparent volume of distribution (Vd beta) was 0.58 litre kg-1, resulting in a terminal half-life of 112 min. Alfentanil concentrations at the time of extubation and postoperative analgesic requirements were also monitored. Good correlation between respiratory depression and plasma alfentanil concentration was found. Neither lower abdominal surgery nor the simultaneous administration of midazolam seemed to affect the kinetics of alfentanil as compared with results from studies in healthy volunteers. The short half-life of alfentanil, resulting from a small volume of distribution, makes it suitable as part of a total i.v. technique. Consideration must be paid, however, to interindividual differences in the pharmacodynamic response and in plasma clearance.

Pharmacokinetics and metabolism of inhaled methyl chloride in the rat and dog

Methyl chloride (MeCl) metabolism and pharmacokinetics were studied in male Fischer 344 rats and male beagle dogs. Apparent steady-state blood MeCl concentrations were proportionate to exposure concentration in rats and dogs exposed to 50 and 1000 ppm. Furthermore, blood MeCl concentrations were similar in both species when they were exposed to the same concentration. A linear two-compartment open model described the blood MeCl data: α and β phase elimination half-times corresponded to approximately 4 and 15 min, respectively, in rats, and 8 and 40 min in dogs. Rats exposed for 6 hr to 0, 50, 225, 600, or 100 [ 14C]MeCl were evaluated for tissue nonprotein sulfhydryl (NPSH), total 14C activity, nonextractable tissue 14C activity, and urinary metabolites. MeCl-induced NPSH depletion was dose-related and was greates in liver. Total 14C in liver and kidney was approximately proportionate to exposure concentrations. Relative concentrations of nonextractable 14C decreased at 600 to 1000 ppm MeCl suggesting a dose-dependent metabolic pathway for MeCl in the rat. Metabolites in urine included N-acetyl- S-methylcysteine, methylthioacetic acid sulfoxide, and N-(methylthioacetyl)glycine. These metabolites are likely to be products of a reaction between MeCl and glutathione. A nonradiometric analysis of a putative MeCl metabolite ( S-methylcysteine) was performed in dogs exposed to MeCl; this method was not a sensitive indicator of MeCl exposure.

Estimation of parameters of linear two-compartment open models with constant intravenous infusion using early blood level data

In previous reports methods of estimating the parameters of the linear one-compartment open model with a constant rate intravenous infusion from early blood level (Barzegar-Jalali, 1981b) and urinary excretion data (Barzegar-Jalali, 1982a) as well as the advantage of the methods have been discussed. In this communication methods of obtaining the parameters of the linear two-compartment open model with constant intravenous infusion from early blood level data are presented. (a) The plasma concentration, C, of a drug with a linear two-compartment open model during a constant rate intravenous infusion is given by Eqn. 1:

Pharmacokinetics of ceftriaxone in humans.

Pharmacokinetics of the investigational cephalosporin ceftriaxone were studied after 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2 g crossed over in 12 normal subjects. Serially collected plasma and urine samples were analyzed for ceftriaxone by high-performance liquid chromatography. Plasma concentration-time profiles were characterized by a linear two-compartment open model with the following respective mean (+/- standard deviation) parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, 6.5 +/- 0.7, 6.2 +/- 0.8, and 5.9 +/- 0.7 h; apparent volume of distribution, 8.5 +/- 1.1, 9.0 +/- 1.1, and 10.1 +/- 1.0 liters; and plasma clearance, 929 +/- 150, 1,007 +/- 130, and 1,190 +/- 150 ml/h. The respective renal excretion parameters were as follows: renal clearance, 373 +/- 60, 399 +/- 50, and 533 +/- 128 ml/h; and percentage of dose excreted unchanged in the 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explained by the concentration-dependent plasma protein binding of ceftriaxone in humans. The impact of the small dose-dependent changes in the pharmacokinetics of ceftriaxone is anticipated to be of negligible clinical significance.

Accumulation in the peripheral compartment of a linear two-compartment open model.

Accumulation factors for the peripheral compartment in a two-compartment open model are derived. These expressions are contrasted with some previously published statements concerning drug accumulation. The utility of the new indices of accumulation is illustrated by reference to studies of gentamicin tissue.uptake and its proposed relation to nephrotoxicity.

Pharmacokinetics of fenbufen in man

The pharmacokinetics of fenbufen (3,4-biphenylcarbonyl proprionic acid) a new antiinflammatory agent, and its metabolites, gamma-hydroxy-4-biphenylbutyric acid and 4-biphenylacetic acid have been studied after oral administration to seven patients with rheumatoid arthritis. Fenbufen was administered as a single oral dose of 600 mg in hard gelatine capsules. A specific, sensitive gas chromatographic method was used to measure the concentration of the three compounds. A linear two-compartment open model appeared suitable to describe the course of the plasma level of fenbufen with time. This compound appeared in the blood after a lag time of 0.45 h and the peak plasma concentration of 5.97 micrograms/ml was observed after 1.19 h. The half-life of plasma disappearance was 10.26 h for fenbufen and 10.07 h and at 9.95 for metabolites II and III, respectively.

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects.

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.

Age-related changes in ouabain pharmacology. Ouabain exhibits a different volume of distribution in adult and young dogs.

To better understand why one must administer much higher doeses of digitalis glycosides to immature than to mature humans and animals, we studied ouabain pharmacokinetics in adult and young dogs. Consistent with reported observations that ouabain-binding, metabolism, and excretion do not change with age, we found no significant differences in the transfer coefficients in a linear two-compartment open model for ouabain pharmacokinetics following a bolus of 0.05 mg/kg. We did find, however, that young dogs had nearly twice the ouabain volumes of distribution per kilogram of body weight as adults (155.4 +/- 1.2 (SE) ml/kg vs. 80 +/- 0.6, P less than 0.0005) and that one could account for this difference with the fact that young dogs had nearly twice the plasma volume 108 +/- 9.8, vs. 68 +/- 7.3, P = 0.001) and interstitial fluid space (318 +/- 35 vs. 190 +/- 6.5, P = 0.006) as the adults. For the same dose per kilogram, left and right ventricular ouabain concentrations were inversely related to the volume of distribution, with the adults having significantly higher tissue levels and incidence of arrhythmias. One must give more ouabain to a young dog to get the same plasma concentration as in an adult because the mass of ouabain in rapid equilibrium with the plasma is diluted in a larger volume of distribution.

Pharmacokinetic analysis of the effect of the ophylline on pulmonary function in asthmatic children

Previously published data of plasma concentrations and pharmacologic effects obtained after rapid intravenous injection and during constant rate intravenous infusion of theophylline in asthmatic children were analyzed pharmacokinetically to determine the relationship between effect on pulmonary function (improvement of forced expiratory volume in the first second) and drug level. The pharmacokinetics of distribution and elimination of theophylline are well described by a linear two-compartment open model consisting of a central and a tissue compartment. There is an essentially linear correlation between the intensity of effect and the logarithm of the amount of drug in the tissue compartment. This correlation exists both with decreasing and increasing drug concentrations, i.e., after intravenous injection and during intravenous infusion of theophylline.

Pharmacokinetics of Highly Ionized Drugs III: Methylene Blue—Blood Levels in the Dog and Tissue Levels in the Rat following Intravenous Administration

Plasma concentrations following rapid intravenous injection of 2-, 5-, 7.5-, 10-, and 15-mg./kg. doses of methylene blue in a dog were obtained. The single-dose data were fit to both a nonlinear heterogeneous one-compartment open model with binding to one type of tissue and the classical linear two-compartment open model. Fitting to the nonlinear model showed no systematic trends in the estimated parameters in relation to dose. Fitting of the concentration data to the classical linear two-compartment open model did show systematic trends in the estimated parameters in relation to dose. Rats were injected intravenously with 2-, 5-, 7.5-, 10-, 15-, and 25-mg./kg. doses of methylene blue and were then decapitated 3min. later. The lungs, liver, kidneys, and heart were removed and assayed. An average of 29.8% of the dose (range 25.2–35.8%) was recovered in those four tissues, indicating very rapid uptake and extensive uptake of methylene blue by tissues. A plot of the average amount taken up by those tissues against the milligrams per kilogram dose was fit by the equation appropriate to the nonlinear model.

Potential Erroneous Assignment of Nonlinear Data to the Classical Linear Two-Compartment Open Model

The classical two-compartment open model implies that if the dose is progressively raised the amount of drug transferred to tissue is directly proportional to dose. A nonlinear model considered in this report assumes that the amount of drug transferred to tissue is a curvilinear function of dose due to a limited capacity of the tissue to bind drug. Simulated (C,t) data, generated from the nonlinear equation appropriate to the model, were found to be fit perfectly or almost perfectly to a double-exponential equation. The usual interpretation would lead to assignment of the classical two-compartment open model. The data reported emphasize the concept that with the limitations of assay sensitivity, several different doses of a drug need to be administered intravenously to elaborate the appropriate pharmacokinetic model.