Pharmacokinetic studies with valproic acid in man.

A specific gaschromatographic assay for the simultaneous determination of valproic acid (dipropylacetate, DPA) and ethosuximide was developed. In 13 epileptic patients only treated with DPA a significant correlation(r = 0.88; p less than 0.01) between the minimal steady state plasma level of DPA and its dose (mg/kg body weight) was found. Plasma protein binding experiments in 3 healthy volunteers revealed a relatively strong binding of approximately 95%. The pharmacokinetics of DPA was evaluated after a single oral solution of 600 mg in 2 healthy subjects. Absorption was rapid with maximum plasma levels of approximately 70 microng/ml within 1--3 h. DPA was eliminated with a half-life of 7.9 and 10 h. Assuming 100% absorption a total plasma clearance of 10--13 ml/min and an apparent distribution volume of 0.13--0.16 l/kg were calculated. The urinary excretion of unchanged DPA is neglegible (1% of dose). It is suggested that the great fluctuations of the plasma concentrations within a dosing interval may be minimized by special galenic formulations.     

Preliminary studies of absorption and excretion of benoxaprofen in man.

1 Benoxaprofen is a new acidic anti-inflammatory compound which was well absorbed after oral administration to man. 2 Single doses of 100, 200 and 400 mg produced mean peak concentrations in the plasma of 13.0, 33.5 and 45.3 microgram respectively, and the plasma half-life of the compound was between 30 and 35 hours. 3 Multiple dosing with 25 and 50 mg every 24 h achieved an equilibrium conentration in the plasma after 6-8 days, while dosing with 100 mg every 12 h enabled equilibrium to be reached in 3-6 days. Plasma concentrations between 35 and 45 microgram/ml were achieved by giving 100 mg doses every 12 hours. 4 Absorption of benoxaprofen was delayed when the drug was given with food, but the total amount absorbed remained the same. 5 The effect of milling the material to small particle size (19 micron) was to increase the rate of absorption compared to that of unmilled material (58 micron). 6 Benoxaprofen was well tolerated by healthy male subject in the doses given.     

Pharmacokinetic studies in man with sparteine

Summary Plasma levels of sparteine were determined in two groups of 8 patients each of whom received 200 mg of sparteine sulphate (Depasan®) intravenously and orally. A method was developed for the determination of sparteine in biological fluids, relying on solvent extraction and gas chromatography. After oral administration, 69.4% of the sparteine was absorbed and peak plasma levels were reached after 46.5 min. After intravenous injection the plasma levels declined with a half life of 117 min. When sparteine is given intravenously, 34.2% of the dose administered is excreted in the urine in the next 24 h as unchanged sparteine. Two metabolites were found in the urine but have not yet been identified. They contribute only a few percent to the total urinary excretion of sparteine. Approximately 50% of sparteine is bound to plasma proteins. — The pharmacokinetics of sparteine after intravenous administration can be described in terms of a one-compartment model. —The tissue distribution of sparteine was studied in preliminary experiments in rats. The drug was accumulated in several tissues, with the greatest concentration in the lungs. The hypothesis is advanced that drugs, which are organic bases with high pKa-values and high lipid solubility, are concentrated mainly in the lungs, followed by the adrenals, spleen, and the heart.     

Pharmacokinetic and pharmacological studies with tolamolol in man.

Pharmacokinetic and physiological variables were measured in six healthy subjects after intravenous and oral administration of tolamolol. 2. After intravenous injection of tolamolol (20 mg), there was a biphasic decline both in plasma concentration and attenuation of maximum exercise tachycardia. First and second phase half-lives of plasma concentration were 7 min and 2.5 h respectively. WReduction of maximum exercise tachycardia declined from 32 beats/min at 2 h to 19 beats/min at 8 hours. Clearance of tolamolol from blood ranged from 0.8-1.41 min-1. 3. After the oral administration of tolamolol (100 mg), the average volume of distribution was 220.1 and plasma concentration half-life 1.8 hours. After ten eight-hourly doses of 100 mg there was no accumulation of tolamolol and the half-life of plasma clearance was unchanged. 4. Hydroxytolamolol was detected in plasma in two of six subjects after oral tolamolol. 5. There was a significant positive correlation between reduction in maximum exercise heart rate and logarithm of plasma concentration of tolamolol after both oral and intravenous administration.     

Pharmacokinetic studies in man with gallamine triethiodide

Summary Plasma concentrations of gallamine were determined in 6 patients undergoing anaesthesia for elective surgery receiving a single intravenous bolus dose of 2 mg/kg and in a further 11 patients requiring additional doses (0.5 to 2 mg/kg) of the relaxant. The two-compartment open model was found to characterize adequately both the single and multiple dose data. No significant differences were noted when the model-independent pharmacokinetic parameters between the two groups of patients were compared with the exception of the distribution phase half-life (t_1/2) (6.70 min single vs 9.19 min multiple, p<0.05). Mean values for the pooled data for the half-life (t_1/2), plasma clearance (Cl_p) and volume of distribution (V_d) were 134.58 min, 1.20 ml/min/kg and 225.28 ml/kg respectively. Evoked twitch response was monitored in each patient to assess the degree of neuromuscular blockade. In only one patient was the bolus dose sufficient to produce complete (100%) blockade, thus the degree of maximal response varied between 78 to 100% and took some 3 to 10 minutes after dose administration. The concurrently measured gallamine plasma concentrations ranged from 9.30 to 19.20 µg/ml. Linear regression of the offset data (20 to 80% paralysis) in 10 patients revealed a recovery rate of 0.35 to 1.33%/min. For 5 patients where offset data was available over the entire range of response (0 to 100%) the calculated mean effective plasma concentrations for gallamine at 50 and 95% paralysis (EC_p50, EC_p95) were found to vary between 3.43 to 10.28 µg/ml, and 5.66 to 23.37 µg/ml respectively.     

Pharmacokinetics of nortriptyline in man after single and multiple oral doses: The predictability of steady-state plasma concentrations from single-dose plasma-level data

Summary Six healthy volunteers were given nortriptyline (NT) in single (1 mg/kg) and multiple (0.4 mg/kg) oral doses with the purpose to study the pharmacokinetics of NT in plasma. The single-dose plasma levels in 3 subjects were applied to a two-compartment open model (Model II) which might be suitable for the disposition kinetics of NT. There were significant (P<0.0005) interindividual differences in the observed mean steady-state plasma concentration,C-0304;, of NT which ranged from 51.7 to 111.0 ng/ml.C-0304; was better correlated to the single-dose plasma clearance rate of NT (r=0.98;P<0.0005) than to the single-dose plasma half-life, (t 1/2), (r=0.89;P<0.05). Thus the steady-state plasma level can be accurately predicted from single-dose studies. The apparent volume of distribution of NT at pseudodistribution equilibrium, (V _d), varied between 21.1 and 31.1 lit./kg body weight assuming complete absorption of the administered dose. There was no significant correlation (r=0.56) between the single-dose and post steady-state plasma half-lives of NT within individuals. NT does not seem to affect its own metabolismin vivo in man since the single- and multiple-dose plasma clearance rates of the drug were similar within subjects. It is concluded that there might be interindividual differences in both the apparent elimination rate and in the distribution of NT. This may be of importance in the pharmacogenetics of NT.     

Pharmacokinetic studies of alizarin in man

Alizarin, a constituent of the madder root, is employed in phytotherapy to prevent recurrences of calcium-containing urinary stones. Pharmacokinetic studies were carried out in human subjects during the development of a pharmaceutical product containing alizarin. After giving a single oral dose of 210 mg of alizarin there were two maxima in the serum concentration curves, the first at 2-4 h and the second at 6-8 h. Alizarin and its glucuronide conjugate were detected in both maxima by TLC. The mean elimination half-life was 12 h. The amounts excreted in the urine within 6 days ranged from 18.1 to 36.3%, and the amounts in the faeces from 21.6 to 33.0% (total recovery: 40-60%). In bile from a patient who had undergone cholecystectomy only 0.6% of the dose was recovered. To exclude any possibility that alizarin might be bound to calcium ions in bone, bone trephine specimens were examined from patients with oxalate stones who had previously been treated with alizarin for several years. No alizarin was detectable in these samples. When alizarin is mixed with fresh human faeces and incubated anaerobically it undergoes rapid bacterial decomposition. This in vitro experiment indicates that when alizarin is given orally a large proportion is broken down by bacterial action in the intestine.     

Pharmacokinetic studies with chlorthalidone (hygroton®) in man

Summary The kinetics of chlorthalidone in blood and urine were analysed in one group of 6 healthy volunteers after single oral doses of 50, 100 and 200 mg, as well as in a second group of 6 volunteers during and after daily oral doses of 50 mg for 14 days. The mean maximal concentrations recorded in blood 8 h after the three different doses were 3.15 µg/ml (SD±0.52), 5.55±1.58 µg/ml and 7.93±1.40 µg/ml, respectively. Disappearance of chlorthalidone from blood followed an apparent first order type of reaction, the average half life t₅₀ being 49 h (SD 11 h). Total renal elimination of unchanged chlorthalidone amounted to 53.3±8.7%, 46.1±8.4% and 34.0±7.3% of the single 50, 100 and 200 mg doses. Between the 6th and 14th days of daily treatment the concentration at the end of the 24 h dose interval was 7.2±1.4 µg/ml (± 1.4) in blood and 186±44 ng/ml in plasma. Except in the early absorption phase after each dose, the distribution of chlorthalidone between erythrocytes and plasma was constant, the average plasma concentration being 1.38±0.28% (n=75) of the whole blood concentration. At steady state during daily dosing with chlorthalidone 50 mg, the renal elimination of unchanged chlorthalidone within each 24 h dose interval was 57±11.2% of the daily dose. The renal plasma clearance ranged from 46 to 70 ml/min. Following termination of repeated administration the concentration of chlorthalidone in blood decreased with a t₅₀=50±5 h and in plasma with t₅₀=49±4.8 h.     

Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic scale-up: accurate prediction of human pharmacokinetic profiles from animal data

Ceftizoxime pharmacokinetic parameters from mice, rats, monkeys, and dogs were scaled allometrically and used to predict the value of each parameter in a 70-kg human. Three methods of interspecies pharmacokinetic scale-up provided accurate simulations of the human biexponential serum concentration-time profiles for a 1-g iv bolus and a 4-g, 30-min intravenous infusion. Successful scale-up of animal pharmacokinetic data can have tremendous impact during the preclinical assessment of new pharmaceutical compounds by providing reasonable estimates of pharmacokinetic parameters in humans.     

Disposition and metabolism of benoxaprofen in laboratory animals and man.

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.     

Pharmacokinetic and pharmacodynamic studies in man with an antianginal agent 'Visacor'

This randomized, double-blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 ('Visacor'), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre-dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4-min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed. Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration-time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7.8 to 17.4 beats min-1 at 24 h, p less than 0.01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.     

Pharmacokinetic characterization of mitonafide in man.

The pharmacokinetic behavior of mitonafide after intravenous administration (1 h infusions) to patients (118-180 mg/m2) can be described by an open three compartment body model. Mitonafide distributes quasi-instantaneously in a central distribution volume of 102 l/m2 (median) from which it equilibrates with two peripheral compartments of 106 and 258 l/m2, respectively. Its disappearance from plasma is triexponential with half-lives of 0.28, 2.0 and 26.9 h, resulting in a clearance of 69 l/h/m2. This clearance is mainly due to the biotransformation of mitonafide leading among others to amonafide, N-acetyl-amonafide, and N-desmethyl-amonafide, which build up substantial concentrations in plasma. Their quantitative importance in terms of exposures (AUC) relative to the parent compound are 86, 197 and 28%, respectively. Terminal elimination from plasma proceeds with half-lives of 34.3, 17.6 and 27.5 h.     

Pharmacokinetic and bioequivalence studies of trospium chloride after a single-dose administration in healthy Chinese volunteers

The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.     

Pharmacokinetics of rapamycin: single-dose studies in the rabbit.

The pharmacokinetics of rapamycin was investigated in five New Zealand white rabbits following intravenous administration of 0.05 and 0.5 mg/kg rapamycin in a randomized crossover fashion. Whole blood concentrations of rapamycin were analyzed by high-performance liquid chromatography (HPLC). Model-dependent and -independent parameters were calculated. The volume of distribution at steady state and total body clearance increased significantly as the dose increased. Rapamycin pharmacokinetics appear to be nonlinear. The whole blood volume of distribution, especially at the higher dose, indicated distribution out of the blood component. The drug is not cleared rapidly, with a terminal half-life of > 13 hours as calculated by model-independent parameters. The 24-h whole blood trough concentrations of the drug are well within the analytical range of the HPLC procedure. This should permit trough level monitoring for therapeutic range studies involving the drug.     

Pharmacokinetic and pharmacodynamic studies in man simulating acute and chronic treatment with oral pirenzepine

Summary Nine healthy, male subjects received controlled-rate i.v. infusions of a new formulation of pirenzepine to produce constant plasma levels of 40 ng/ml and 105 ng/ml. They also received stepped infusions resulting in plasma levels of 20, 40, 80 and 40 ng/ml for defined periods.Peptone-stimulated gastric acid and volume secretion and near point vision decreased dose dependently, whereas gastric acidity was unchanged. There was a significant correlation between inhibition of gastric acid secretion and the pirenzepine concentration in plasma and in gastric juice. During the stepped i.v. infusion, changes in near point vision were closely related to the plasma drug concentration. Antimuscarinic side-effects occurred more frequently when the plasma drug level was high.Overall, there was a close relationship between the plasma concentrations and the effects and side-effects of pirenzepine. Its gastric inhibitory action was characterized only by a reduction in gastric volume secretion. Increasing plasma concentrations during the first days of treatment may be essential for its efficacy as an antiulcer drug.     

Tolerability and serum levels of benoxaprofen in healthy volunteers

Tolerability, serum levels and urinary excretion of benoxaprofen (B) in therapeutic doses of 400 or 600 mg as a capsule were studied in 22 healthy volunteers after single or multiple doses. B was determined by a HPLC procedure. Apart from a skin reaction in one patient, no major problems were encountered by patients. Mean serum peak values after 400 and 600 mg were 49.84 and 94.54 micrograms/ml respectively. Mean time to peak was 5.6 hours and mean half-life ranged between 45.38 (400 mg regimen) and 63.48 hours (600 mg regimen). Urinary excretion was only a fraction of the doses ingested: 14.39% after a single dose; 35.5% after multiple doses. This may depend on other pathways of elimination of the drug because steady state is reached according to half-life.