Pharmacokinetics of teicoplanin in man after intravenous administration

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3-mg/kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 micrograms/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the lambda 1 phase was 20.3 min, that of the lambda 2 phase was 2.9 hr, and the half-life of the estimated lambda 3 phase was 40.5 hr, in good agreement with that of the lambda z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 micrograms/ml) on many pathogenic organisms for at least 1 day after administration.     

Pharmacokinetics of amiodarone after intravenous and oral administration

Summary Seven patients with cardiac arrhythmias were given amiodarone 400 mg intravenously over 2 min, and 2–4 days later the same dose was given orally. The serum concentration of amiodarone was determined by HPLC; the sensitivity of the analysis was 0.1 µg/ml. The time sequence of the measurements of drug concentration made conventional compartemental analysis impossible. There was large individual variation but some of the curves suggested enterohepatic circulation. The time from oral intake to the peak serum concentration was estimated to be 7.3±2.9 h (SD). The amount of drug reaching the general circulation in 24 h after oral intake averaged 42% (22–80%). After oral administration of amiodarone 200 mg 8 hourly the serum concentration before the morning dose averaged 0.61 µg/ml after 24 h, 0.76 after 48 h, 1.18 after 1 week and 1.56 µg/ml after 1 month. In one patient, who had been on amiodarone therapy for 8 months, the drug was discontinued and the serum concentration was followed over the next 3 months. The drug elimination curve suggested an elimination half life of 13.7 days. Because of instability in physiological saline protein binding could not be precisely quantitated, but only characterized as strong. No unchanged amiodarone was found in urine. The urinary excretion of iodine over 2 h after intravenous administration suggested that 5% of orally administered amiodarone was eliminated in the urine after biotransformation. No effect of the drug was observed during the first 10 days of treatment. In 2 patients with supraventricular arrhythmia, an excellent response was seen, and in one with ventricular arrhythmia there was a good response.     

Pharmacokinetics of teicoplanin in man after intravenous administration

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3- mg/ kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 g/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the ₁ phase was 20.3 min, that of the ₂ phase was 2.9 hr, and the half-life of the estimated ₃ phase was 40.5 hr, in good agreement with that of the _Z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 g/ml) on many pathogenic organisms for at least 1 day after administration.This work was supported in part by a grant from Gruppo Lepetit, Milan, Italy, and by a CNR (National Research Council, Rome, Italy) grant on Clinical Pharmacology and Rare Diseases.This work was presented in part at the 13th International Congress of Chemotherapy, Vienna, August 28 to September 2, 1983.     

Pharmacokinetics of pentobarbital after intravenous and oral administration

The plasma levels in humans of pentobarbital were determined after intravenous administration of a 50 mg dose. It was found that pentobarbital is distributed in at least two kinetically distinct body compartments: a central, or “serum” compartment and a peripheral, or “tissue,” compartment. By use of established mathematical techniques, values were assigned to the rate constants controlling the distribution and overall elimination of the drug from the body. The oral absorption of pentobarbital in fasted and nonfasted subjects was determined by mathematical analysis of the plasma level data following oral administration of a 50 mg dose. It was found that the presence of food significantly reduces the apparent absorption rate constant but not the amount absorbed. The absorption of a second dose, given 1.5 hr after the first dose, in nonfasted subjects was not affected, and a rapid increase in plasma levels occurred after this administration.     

Pharmacokinetics of bretylium in man after intravenous administration

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitation in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t_1/2)of 7.8 hr and apparent volume of distribution (V_d,)of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.This work was supported in part by a grant from Arnar-Stone Laboratories, Inc., McGaw Park, Illinois.     

Pharmacokinetics of falipamil after intravenous administration to humans

Falipamil (2-[3-[3-(3,4-dimethoxyphenetylmethylamino]propyl]-5,6- dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans (n = 6) was determined in plasma and urine after iv administration of 100 mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 +/- 3.7%, with 68.2 +/- 4.3% in urine and 23.6 +/- 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48 h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is approximately 100 times less active than 1, contributed 14.1 +/- 1.6 and 4.5 +/- 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 +/- 1.2 (concentration range: 2000-8000 ng/mL) and 89.7 +/- 0.5% (concentration range: 62.5-1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2 min at 724 +/- 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (beta-phase) of 1 from plasma was 1.8 +/- 0.6 h (range 1.4-2.9 h), mean residence time was 2.4 +/- 0.4 h, total body clearance was 1108.5 +/- 119 mL/min, and renal clearance was 117 +/- 20 mL/min. All parameters demonstrated very low intersubject variability.     

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 14C-fenflumizole after intravenous administration to man

The disposition of 14C-labelled fenflumizole was studied in five healthy subjects who received 0.1 mg/kg of fenflumizole as single intravenous doses. Radioactivity was measured in whole blood, plasma, urine and feces from prior to until 168 hours after dose administration. Chemical determinations of fenflumizole and its two demethylated derivatives in plasma were made by HPLC followed by fluorescence detection. Concentrations of fenflumizole calculated from radioactivity in plasma were consistently higher than from chemical determinations, suggesting the presence of metabolites. Radioactivity in blood cells decreased more slowly than in plasma. Plasma concentrations versus time could be described by a four-compartment model, with a terminal half-life of 119 hours (median). About 50% of the dose was excreted with the faeces, and about 4% was recovered in the urine. Unchanged fenflumizole in the urine accounted for 0.0001% of the total dose. Renal clearance of radioactive material decreased at low concentrations of radioactive compound in plasma, which may indicate changes in unbound fraction of drug and metabolites, or a saturable tubular reabsorption process. The slow elimination of fenflumizole is consistent with slow release from tissues and/or enterohepatic recycling.     

Pharmacokinetics of ranitidine after intravenous administration in hemodialysis patients

The pharmacokinetics of ranitidine and its removal by hemodialysis were determined in 9 patients with chronic renal failure requiring hemodialysis. Ranitidine (50 mg) was administered as an intravenous bolus at the beginning of the dialysis procedure, which lasted for 4 h. The elimination half-life, plasma clearance and volume of distribution (VD area) of ranitidine in these patients were 9.0 +/- 2.6 h (mean +/- SD), 305 +/- 152 ml/min and 3.5 +/- 1.9 liters/kg, respectively. About 8% of the administered dose was removed during a single dialysis procedure. The elimination of ranitidine is appreciably reduced in these patients. These results suggest that the dose of ranitidine should be adjusted in patients with severe renal failure who are undergoing hemodialysis, and a suitable schedule for dosing such patients is suggested.     

Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.     

Pharmacokinetics of valproic acid after oral and intravenous administration

1 The kinetics of sodium valproate (di-n-propyl-acetate, Depakine®) have been studied in six healthy volunteers after administration of single oral and intravenous doses (800 mg).

2 Kinetic parameters were similar for both routes of administration. In all subjects absorption was rapid and complete. Half-lives ranged from 11-15 h. Apparent volumes of distribution were relatively low (0.147 ± 0.004 l/kg) and showed little variation amongst individuals.

3 The factors responsible for the poor correlation between dosage and serum levels during chronic treatment and therapeutic implications are discussed.

     

Pharmacokinetics of glycyrrhizin after intravenous administration to rats.

A simple high-performance liquid chromatographic method was developed to study the pharmacokinetics of glycyrrhizin in the rat after bolus intravenous administration at a dose of 20, 50, or 100 mg/kg. The decline in the concentration of glycyrrhizin in plasma was generally biexponential at each dose, but the terminal disposition became much slower as the dose was increased. A greater-than-proportional increase in the glycyrrhizin concentration in plasma was observed with an increase in the dose, a result suggesting a dose-dependent glycyrrhizin disposition. The disposition of drug in plasma at each dose fitted well to a two-compartment pharmacokinetic model. The apparent total body clearance decreased significantly with increases in the dose. On the other hand, the apparent distribution volume after intravenous administration was unaffected by the dose. The results indicate that the pharmacokinetics of glycyrrhizin is nonlinear.     

Pharmacokinetics of metformin after intravenous and oral administration to man

Summary The kinetics of¹⁴C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of flip-flop type for oral metformin.     

Pharmacokinetics of tranexamic acid after intravenous administration to normal volunteers

Summary The pharmacokinetics of tranexamic acid has been investigated in two healthy volunteers. The behaviour of the drug can be described in terms of a two compartment open model; the disposition (biological) half-life was 2.7 h and 1.9 h, respectively. In five normal volunteers the mean total recovery in urine 48 h after dosing was 94.8%. The renal clearance in the two subjects, adjusted to 1.73 m² body surface area, was 135 and 132 ml/min/1.73 m², respectively, indicating that tranexamic acid is eliminated by glomerular filtration and that neither tubular excretion nor absorption takes place.     

Pharmacokinetics of dihydroergosine in rats after intravenous and oral administration

Wistar rats received an intravenous dose of 20 micrograms/kg and an oral does of 40 micrograms/kg 3H-Dihydroergosine. Concentrations of radioactivity were measured in plasma, bile, urine, and faeces, and pharmacokinetical parameters of an open two compartment model were calculated. After intravenous injection and oral administration 3H-Dihydroergosine is rapidly lost from the central compartment with distribution rate constants alpha = 0.889 h-1 and beta = 0.722 h-1, respectively. Biological half life in the elimination phase after both application is nearly the same t 1/2 = 13.6 h. The volume of central compartment is Vc = 3.075 l/kg and the volume of distribution Vd beta = 30.75 l/kg. The fraction of 3H-Dihydroergosine absorbed after oral administration, calculated from areas under the curves upon oral and intravenous administration, is 31%. The percentage of 3H-radioactivity eliminated with bile was 98.3% of the dose within 72 hours after intravenous and 29.3% after oral administration. The main portion of the administered 3H-radioactivity was recovered in faeces -66.1% after intravenous and 81.3% after oral administration, while only 17.4% and 4.9% of the administered dose was eliminated in the urine within 120 hours, respectively.     

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers

Summary The pharmacokinetics of xamoterol, a -adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design.After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min^–1 and the volume of distribution at steady-state (V_ss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose.Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.