Compartment Open Model Research Articles

Pharmacokinetics and metabolism of sulphadiazine in neonatal and young pigs.

The pharmacokinetics of sulphadiazine was studied in newborn, 1 week, and 8 weeks old piglets after intravenous administration of 60 mg/kg. Kinetic parameters were calculated using a two compartment open model. Steady state volume of distribution averaged 0.62, 0.56, and 0.48 1/kg at birth, 1 week, and 8 weeks, respectively. Elimination half-life decreased from 455 min. at birth to 322 min. at 1 week and 157 min. at 8 weeks leading to a rise in body clearance from 0.99 to 2.20 ml/min./kg during the same age period. Urinary excretion data indicated that the increase in body clearance reflects maturational changes in both renal function and metabolic capacity. Although renal clearance increased several times more than metabolic clearance, metabolism remained the main contributor to elimination of SDZ at all ages. Metabolism of SDZ involves two important pathways - acetylation and aromatic hydroxylation; the former being well developed at birth, while the latter increased markedly during the age period studied.

Pharmacokinetics of the mycotoxin penicillic acid in male mice: Absorption, distribution, excretion, and kinetics

The pharmacokinetics of penicillic acid (PA), a carcinogenic mycotoxin, was investigated in male mice. Absorption of PA after po administration of [ 14C]PA was rapid. Only a small percentage of the radioactivity in the plasma was unchanged PA. After ip or iv administration of [ 14C]PA (90 mg/kg), blood, liver, kidneys, intestine, lungs, heart, and spleen contained the largest amounts of radioactivity while brain tissue accumulated the least. Over 90% and approximately 60% of the administered radioactivity was excreted in the urine after iv and ip injection, respectively, but essentially no unchanged PA was detected in the urine. Over 25% of the administered radioactivity following an iv dose of [ 14C]PA (90 mg/kg) was excreted in the bile in 60 min; no unchanged PA was detected in the bile. The excretion of radioactivity in the bile was decreased in diethyl maleate-pretreated mice. Only a small amount of the administered radioactivity was recovered in the feces and as expired CO 2. The unchanged PA concentration-time curve in plasma was best fit by three, two, and one compartment open models after iv, ip, and po administration, respectively. Based on these results, it was concluded that metabolism and not excretion of unchanged parent penicillic acid is the major process of elimination of PA from the blood. There are extensive route-dependent differences in the kinetic behavior of PA.

DELAYED PLASMA CLEARANCE OF FUROSEMIDE WITH MULTIPLE DOSING IN NEONATES

The effect of repeated dosing of IV furosemide (F) on the drug's kinetic profile was evaluated in two groups of neonates; 8 babies with pulmonary edema or fluid overload who received F for the first time (bt wgt 2.3±3 g, gest age 35.0±1.0, postconceptional age 36.6±1 wk) and 7 neonates who received a repeat dose of F, (bt wgt 1.8±0.4, gest age 31.7±2.2, postconceptional age 34.6±2.0 wk), 24-48 hrs after the first dose. Clinical data were not significantly different in between groups. Blood samples for F measured by HPLC were obtained before and at times 1,2,3,6,9,12,24 h after F. Kinetic data were calculated assuming a one compartment open model using areas under the time concentration curve. Data show that repeat doses of F leads to a higher plasma concentration (corrected for pre-drug concentration) contracted volume of distribution and decreased plasma clearance. We postulate that the initial dose saturates tissue binding sites leading to higher drug concentrations and decreased plasma clearance with subsequent doses. Frequent repeat doses of F may lead to plasma drug accumulation in the neonate.

IMIPENEM PHARMACOKINETICS IN CHILDREN

Imipenem (Im) (thienamycin, MKO787/MKO791), a new β-lactam antibiotic, has outstanding potency against gram positive, gram negative, aerobic and anaerobic bacteria, including Pseudomonas aeruginosa. Selected pharmacokinetic and safety parameters were studied in children in anticipation of clinical therapeutic trials. A single dose (10 or 25 mg/kg) of Im was given intravenously to eight children aged 2-12 years hospitalized and receiving conventional intravenous antibiotics for suspected or proven infection. Plasma samples were obtained at 1 min, 30 min, 1, 2, 4, and 6 hours after the completion of the Im infusion. Random urine samples were also obtained. Im concentrations were measured by high performance liquid chromatography. Interpretation of the data was based on a one compartment open model. Selected parameters (means ± S.D.) are as follows: No adverse clinical or laboratory effects were noted. Based on these data and Im's in vitro activity, a dose of 25 mg/kg, intravenously every 4-6 hours, would likely be safe and provide therapeutic serum and urine concentrations in clinical trials in pediatric patients.

Quinidine-induced rise in ajmaline plasma concentration.

A high-performance liquid chromatographic method is described for the simultaneous determination of ajmaline and quinidine in human plasma. With 0.5 ml plasma sample of a ajmaline and quinidine, concentrations as low as 0.001 and 0.01 micrograms ml-1, respectively, could be detected and the technique could be used to investigate the effect of quinidine on the pharmacokinetics of ajmaline. Four healthy subjects were given oral ajmaline (50 mg) alone or in combination with quinidine sulphate (200 mg) on separate occasions. When ajmaline was administered alone, its plasma concentrations were less than 0.03 micrograms ml-1. Quinidine induced a marked increase to give a mean peak concentration of ajmaline which increased from 0.018 micrograms ml-1 after a single administration to 0.141 micrograms ml-1 in combination with quinidine. the area under the ajmaline concentration-time curves was increased 10 to 30-fold by the concurrent administration of quinidine. According to the one compartment open model, the absorption rate constant of ajmaline did not change appreciably, but the elimination rate constant was reduced to approximately 50% of the value in the absence of quinidine. The results indicate the existence of a significant interaction between oral ajmaline and quinidine.

Pharmacokinetics of tolfenamic acid: disposition in bile, blood and urine after intravenous administration to man.

To study its pharmacokinetics and especially microCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7-10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V1 of 3.67 +/- 0.681 and VSS of 8.0 +/- 1.01. The total plasma clearance of tolfenamic acid averaged 106 +/- 8 ml/min and t1/2 beta was 1.38 +/- 0.32 h. A three compartment open model was required to describe the kinetics of total 14C. The plasma clearance of total 14C was 15.4 +/- 3.9 ml/min and its terminal half life averaged 19.0 +/- 4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1 +/- 0.3% of the dose, whereas the recovery of total 14C was 18.6 +/- 4.9%. The biliary clearances of tolfenamic acid and total 14C were 1.2 +/- 0.3 and 5.0 +/- 2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.

Absorption of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, in rats and dogs.

Plasma levels of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, were determined by a radioimmunoassay after oral or intravenous administration in rats and dogs. A pharmacokinetic analysis after intravenous injection revealed biphasic elimination of the plasma concentration following a two compartment open model with half lives in alpha-phase of 2.0 min and beta-phase of 19.2 min in rats, and half lives in alpha-phase of 4.0 min and beta-phase of 33.0 min in dogs. Absolute bioavailabilities when administered orally the solution of DN-1417 after 24 h fasting in rats and dogs were 1 and 10%, respectively. The bioavailability was observed to be unchanged at the dose up to 500 mg/kg in rats and at the dose up to 100 mg/dog in dogs. Thus, the absorption of DN-1417 in rats and dogs was proportional to the dose. On the other hand, the absolute bioavailabilities after meal in dogs were 7.9% at the dose of 20 mg/dog and 7.2% at the dose of 2 mg/dog, whereas in the 24 h fasting condition they were 15.7 and 12.0%, respectively, showing the decrease in absorption with food ingestion. These phenomena are somewhat different from the absorption of thyrotropin-releasing hormone.

The role of prostaglandins for norepinephrine clearance in borderline hypertension

Studies were done to determine the role of endogenous prostaglandins (PGs) for norepinephrine (NE) clearance in 10 male borderline hypertensives (BHT) (age: 20-28) and six age-matched male normotensives (NT). Two experimental protocols were followed in these subjects: 10 min orthostasis with blood sampling (protocol I), and 100 ng/kg/min of L-NE infusion for 60 min at supine position. Blood was collected from indwelling catheter at every min for 10 min after stopping the NE infusion (protocol II). Plasma NE was measured by THI method using HPLC. Disappearance curve of plasma NE was analyzed following the two compartment open model. The orthostasis and the steady state NE infusion were repeated after 150 mg/day of indomethacin (Ind) for three days. There were significant increases in plasma NE after orthostasis in both groups: from 180.8 +/- 28.0 pg/ml to 346.2 +/- 78.0 pg/ml (p less than 0.05) in NT and from 120.1 +/- 12.8 pg/ml to 289.6 +/- 20.3 pg/ml (p less than 0.001) in BHT, but there were no significant differences between the two groups. Ind pretreatment did not alter these responses. The calculated half-time of the first exponential phase (T 1/2) was 1.50 +/- 0.07 min in NT which decreased to 0.98 +/- 0.10 min (p less than 0.05) after Ind pretreatment. In BHT, T 1/2 was 1.03 +/- 0.08 min (p less than 0.01 vs NT), which was not significantly changed after Ind. These results may suggest that endogenous PGs have some role(s) in NT for NE clearance, probably exerting inhibitory action on neuronal uptake. In BHT, neuronal uptake of NE is increased, probably due to an adaptation mechanism to elevated blood pressure.

A calculator package for pharmacokinetic application

A calculator program package is given for the computation of the parameters of two different pharmacokinetic models: the ‘one compartment open model’ with first order absorption, and the ‘two compartment open model’ with rapid intravenous injection, using the peeling method. If parameters are known, simulation of these systems can be done for single and repetitive doses. The package includes an area under curve ( AUC) program for the evaluation of clearance. The algorithms were applied for TI 58,59 and HP 97 calculators and they can be widely used in clinical practice.

Quinine disposition kinetics.

Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1.

Pharmacokinetic study of methyl glyoxal-bis-guanylhydrazone (methyl-GAG).

Using a paired ion exchange high pressure liquid chromatographic assay, pharmacokinetic evaluation of methyl glyoxal bis guanylhydrazone (methyl-GAG) was performed in nine male New Zealand albino rabbits following administration of a single intravenous bolus dose of 50 mg/kg B.W (550 mg/m2 BSA). Blood samples were collected before and at intervals of 5, 10, 15, 30 min and 1, 2, 3, 4, 6, 8, 12, 18, and 24 h after administration of the drug. The analysis of experimental data indicates a three compartment open model with first order elimination from the central compartment described by the equation Cpt = A.e-alpha t + B.e-beta t + C.e-gamma t, where A, B, C, are 107.985, 4.785, and 0.763 micrograms/ml, respectively. alpha, beta, gamma, are 5.466, 0.487, and 0.030 h-1, respectively, and T1/2 alpha, beta, gamma are 7.6, 85.3 min and 23.1 h, respectively. The mean volume of distribution in the central compartment Vc was 0.44 liters (1)/kg, volume of distribution Vdarea 30.326 1/kg, and the total body clearance 0.9097 1/kg/h. The existence of a long terminal plasma half life of methyl-GAG reported previously in human studies was also confirmed in experimental animals and may explain the cumulative toxicity of this drug.

Pharmacokinetics of chlorazepate after intravenous and intramuscular administration.

Dichlorazepate (DPC) was given to eight healthy volunteers aged 22-38 years (five males and three females). The dose was 20 mg (48.9 mumol) given either as an IV or an IM injection. The interval between the injections was at least 1 week. Plasma samples were analysed for desmethyldiazepam (DMD) by HPLC before and after acid hydrolysis. The kinetics after both IV and IM administration could be explained by a one or two compartment open model. By comparing values before and after hydrolysis an estimate of di- and/or monopotassiumchlorazepate (MPC) could be made. The bioavailability was almost 100% after IM administration. The plasma half lives of DPC and DMD were independent of the form of administration (2.42 and 46.0 h respectively after IV and 2.29 and 45.1 h respectively after IM injection).

Pharmacokinetics of 5,6-dihydro-5-azacytidine (NSC-264880) in the foxhound.

An HPLC analytical method was applied to the determination of plasma concentrations of 5,6-dihydro-5-azacytidine (NSC 264880, DHAC) in two foxhounds after a rapid intravenous infusion of 300 mg/kg DHAC. The dose employed is the mouse equivalent LD10 dose which results in mild reversible toxicity in the dog. The decline in DHAC plasma concentrations was greater than three log decades after dosing. The plasma concentration-time data was computer-fitted by NONLIN to a three compartment open model with first-order elimination using the equations for a short intravenous infusion. The half-lives corresponding to the three exponential phases were: t1/2 alpha = 5.78 min, t1/2 beta = 1.57 h and t1/2 gamma = 22.0 h in dog 1 and t1/2 alpha = 7.41 min, t1/2 beta = 2.25 h and t1/2 gamma = 21.6 h in dog 2. The terminal phase of the plasma concentration time profiles represented a minor contribution (2.2-3.2%) to the total area under the curve. The plasma concentration time data for the first 12 h after dosing was computer fitted to a two compartment open model. The initial and terminal half-lives determined from the two compartment fits were similar to the t1/2 alpha and t1/2 beta values of the fits to the three compartment open model. Similar total body clearance values were calculated from the areas under the plasma concentration time curves from time zero to infinity for the computer fits to the three and two compartment models, respectively. Thus, for practical purposes, it appears feasible to define adequately the total body clearance of DHAC by analysis of the plasma concentration time data during the time interval in which the plasma concentration is described as a bi-exponential equation. Renal excretion of the parent drug is the principal route of excretion of DHAC from the dog.

Biological variability of multiple dose pharmacokinetics of netilmicin in man.

Intra- and interindividual variability in the serum kinetics and renal elimination of netilmicin was investigated in a controlled study in 6 healthy, male volunteers. The antibiotic was administered on 2 single days, separated by a 3 week interval. Netilmicin 2 mg/kg lean body mass was given i.m. twice (b.i.d.) and three times (t.i.d.) in a crossover design. 54 blood and 28 urine samples per volunteer were analysed by a radio-enzymatic assay. 24 h serum kinetics were best described by a two compartment open model with time-dependent serum clearance. The latter decreased intraindividually on both study days, from a mean of 82 to 68 ml/min (p<0.05). A similar decrease was observed in the 12 h creatinine clearance. Because drug administration started in the morning, this finding reflects the physiological circadian rhythm in the glomerular filtration rate. The corresponding half-lives of netilmicin rose from 149 to 171 min. Striking intraindividual variation in absorption half-life was observed in all volunteers, ranging from less than 4 to more than 30 min. Comparison of the pharmacokinetic parameters derived from data of the first and second study, revealed a significant intraindividual reduction in the volume of distribution (mean decrease 13%) and in the serum clearance of netilmicin (−8%). Analysis of the serum data of the b.i.d. and t.i.d. dosing schedules showed no difference in the pharmacokinetic parameters; there was significantly higher urinary recovery with the t.i.d. (+9%) than with the b.i.d. schedules. After both days, the 24 h creatinine clearance decreased significantly, by more than 10%. A slight nephrotoxic effect, induced by a therapy for one day with netilmicin, can be deduced from these data.

The effects of porcine GIP on insulin secretion and glucose clearance in the pig

The present study was undertaken with the aims of studying the pharmacological effects and the pharmacokinetics of porcine GIP in pigs in vivo. Infusion of GIP and glucose resulted in a significant increase in the insulin release compared to the insulin release after glucose infusion in the control group. A significant increase in glucose clearance was also seen during GIP infusions. A two compartment open model with first order kinetics was used for the description of the pharmacokinetics of the infused GIP. The plasma half-life for GIP was found to be between 34-35 minutes.

Tele-methylhistamine as an index of the activity of central histaminergic neurons

The activity of histaminergic neurons was examined in various brain regions. Histamine (HA) and tele-methylhistamine (t-MH) were simultaneously assayed using HPLC with fluorescence detector. The HA content was high in the hypothalamus and thalamus and low in the cerebellum and pons-medulla oblongata in the rat, mouse and guinea-pig. The t-MH content was high in the hypothalamus and amygdala in all these species, and was exceptionally high in guinea-pig hippocampus. Pargyline hydrochloride (80 mg/kg, i.p.) increased the t-MH content of the rat brain linearly up to 4 hr after injection. The increments of t-MH (Δt-MH) were large in the hypothalamus, striatum and thalamus (108.7, 80.2 and 62.1 ng/g/hr, respectively), but very slight in the cerebellum (2.9 ng/g/hr). Although relatively high HA levels were observed in the spinal cord, no increase in t-MH was detected after pargyline treatment. There was a significant correlation between At-MH and steady-state t-MH levels in different brain regions (r = 0.82, p < 0.01). The treatment with α-fluoromethylhistidine (50 mg/kg, i.p.) produced 15-60 % depletion of HA 4 hr later in various rat brain regions except for the spinal cord. The percentage of depletion was regarded as that of neuronal HA to the total HA. The half-life of neuronal HA estimated from the methyl-ation rate by a one compartment open model was in a range of 7.7-56.6 min in the following rank order: striatum < hippocampus < midbrain < amygdala < cerebral cortex < pons-medulla oblongata < thalamus < hypothalamus. These results indicate that the t-MH levels and the increments after pargyline treatment are useful as indices of the brain histaminergic function.

Elimination of cefroxadine (CGP-9000) from patients undergoing dialysis.

The pharmacokinetics of cefroxadine was studied in 17 patients with terminal renal impairment, 10 of whom were undergoing 5 h dialysis sessions. The antibiotic was administered as a single oral dose of 500 mg. Cefroxadine followed a single compartment open kinetic model. During the interdialysis period in patients with terminal renal impairment, an average Cmax of 26.59 micrograms/ml and a tmax of 3.65 h were reached, which are greater than in patients with normal renal function. The serum half-life was reduced from 23.55 h in the interdialysis periods to 3.40 h during the dialysis sessions. The average extraction coefficient was 0.249. It is recommended that a 500 mg dose cefroxadine should be administered at the end of each dialysis session if the interdialysis period is 48 h.

67Gallium Kinetics in the Blood of Patients with Malignant Tumors

67Gallium was injected into 60 patients with malignant tumors and into 42 patients in whom malignant tumors had been excluded by clinical investigation. 67Ga kinetics in blood were evaluated by non-linear least square regression computer analysis according to an open 2-compartment model where elimination proceeds from the peripheral compartment. Parameters of 67Ga kinetics in tumor patients showed a bimodal distribution, as was also the case in patients without tumors. No difference could be demonstrated between kinetic parameters of tumor patients and patients without tumors. In 4 patients, 67Ga kinetics could be evaluated before and after treatment of their malignant tumors, but a decrease in the volume of distribution was the single alteration of kinetic parameters occurring after treatment. This decrease may be explained by a smaller peripheral compartment resulting from the loss of tumor mass after treatment. Nevertheless, we conclude that the evaluation of 67Ga kinetics in blood will provide only limited information about the presence, size and growth rate of malignant tumors in man.

Pharmacokinetics of theophylline: a dose-range study.

1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg).

Microbiology, Pharmacology, and Clinical Use of Mezlocillin Sodium

The acylureido penicillin mezlocillin is active against gram-positive, gram-negative, and anaerobic bacteria. It easily penetrates the outer membrane of gram-negative bacteria, and it has a strong affinity for penicillin binding protein 3. Its stability to beta-lactamases is weak. Mezlocillin is synergistic when given in combination with aminoglycoside antibiotics. In pharmacokinetic studies mezlocillin conforms to a two compartment open model; its pharmacokinetic properties are dose-dependent. The half-life of the drug is about 1 hour after intravenous injection and 1.5 hours after intramuscular injection. Protein binding ranges from 16 to 42%, and 55% of a dose is excreted in the urine. Biliary excretion ranges from 0.5 to 25%. Clinical trial cure rates were as follows: bacteremia (78%), respiratory tract (62%), urinary tract (81%), gynecological (86%), bone and joint (55%), intraabdominal (67%) and skin and soft tissue (59%). The frequency of adverse reactions was 7.7%. Interstitial nephritis, CNS toxicity, and bleeding have not been reported.