Dose-Dependent Pharmacokinetics of the Aldose Reductase Inhibitor Imirestat in Man

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steady-state pharmacokinetics of metronidazole in Crohn's disease

The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day-1. Pharmacokinetic indices were found to be independent of the dose administered. The half-life, volume of distribution and oral clearance of metronidazole were 9.5 +/- 2.1 h, 0.732 +/- 0.094 l kg-1 and 0.921 +/- 0.175 (ml min-1) kg-1 (mean +/- SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 +/- 7.4 to 58.9 +/- 5.2. Both plasma and urine data exhibited very large inter-patient variations. However, intra-patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations as well as cumulative urinary excretion of the drug and its metabolites. It is concluded that in Crohn's disease, the pharmacokinetics of MTZ and its metabolites are linear and that the drug concentrations are dependent on the total body weight.     

Pharmacokinetics of magnolin in rats

This study was first conducted to characterize the intravenous and oral pharmacokinetics of magnolin, a major pharmacologically active ingredient of Magnolia fargesii, at various doses in rats. Magnolin was administered to rats by intravenous injection (0.5, 1 and 2 mg/kg doses) and oral administration (1, 2 and 4 mg/kg doses), and serial plasma and urine samples were harvested. Magnolin concentrations were determined by a validated LC/MS/MS assay. After both intravenous and oral administration, the AUCs were linearly increased as the dose increased. Other pharmacokinetic parameters of magnolin (except the V _ss after the intravenous administration) were also independent of the doses. The extent of absolute oral bioavailability ranged from 54.3–76.4% for the oral doses examined. Magnolin was considerably bound to rat plasma proteins and the binding value was constant (71.3–80.5%) over a concentration ranging from 500 to 10000 ng/mL. The pharmacokinetic parameters of magnolin were doseindependent after both intravenous and oral administration. When given orally, magnolin was rapidly absorbed.     

The disposition of chloroquine in healthy Nigerians after single intravenous and oral doses.

The pharmacokinetics of chloroquine after single oral (600 mg) and intravenous (2 mg kg-1) doses were studied in healthy black Nigerian students. The plasma concentrations of chloroquine and its desethylmetabolite were determined using a high performance liquid chromatography technique. Concentrations as low as 3 ng ml-1 were reproducibly determined. After i.v. dosage, the half-life ranged between 144 and 298 h; the total plasma clearance was between 282 and 1130 ml min-1 and the volume of distribution between 142 and 398 1 kg-1. Renal clearance was about 52% of plasma clearance. The estimated total urinary recovery of chloroquine and desethylchloroquine was 77% of the oral dose. There was no significant difference in the pharmacokinetics between the oral and the i.v. administration. The pharmacokinetic properties of chloroquine, in these black subjects did not differ from those previously demonstrated in Caucasians.     

Pharmacokinetics of oxazepam in healthy volunteers.

The pharmacokinetics of oxazepam was studied in healthy volunteers. When oral doses of 15 mg were given to eight subjects on two occasions 2.5 years apart the individual areas under the plasma concentration time curves did not differ significantly. Plasma clearance ranged between 0.050 and 0.171 x kg-1 x h-1 and half-lives from 5.9 to 25 hours. The urinary recovery of oxazepam conjugates was 67 +/- 15 S.D.% of the dose given and the total recovery including faecal oxazepam was 70 +/- 15 S.D. %. On multiple dosing (5 mg t.i.d.) stable steady-state concentrations were established. There was a tendency for slightly lower steady-state concentrations than predicted from single oral doses. During steady-state 86 +/- 17 S.D. % of the dose was recovered in the urine over a 24 hour period.     

Pharmacokinetics and tissue distribution of olanzapine in rats

The single dose pharmacokinetics of olanzapine in rats, following an oral dose and its distribution in the brain and other tissues after repeated oral and intra-peritoneal (i.p.) administration, were studied. Olanzapine in plasma, brain, liver, lung, kidney, spleen and fat was assayed at predose, 0.25, 0.5, 1, 2, 5, 12, 24, 36, 48 h postoral dose of 6 mg/kg and after daily oral and i.p. doses of 0.25, 1, 3, and 6 mg/kg/day of olanzapine for 15 consecutive days by a sensitive and specific HPLC method with electrochemical detection. Olanzapine was readily absorbed and distributed in plasma and tissues as the peak concentrations were reached within approximately 45 min after the oral dose. The terminal half-life of olanzapine in plasma was 2.5 h and in tissues it ranged from 3 to 5.2 h. The area under the concentration-time curve (AUC(last)) was lowest in plasma and largest in liver and lung. The AUC(last) of olanzapine was eight times larger in brain and three to 32 times larger in other tissues than that in plasma. After repeated oral doses, the plasma and tissue concentrations of olanzapine were generally higher than those after repeated i.p. doses. The liver and spleen had the highest concentrations after oral and i.p doses, respectively. In both cases, the tissue concentrations were four- to 46-fold higher than that in plasma and correlated with administered doses. Likewise, plasma concentrations strongly correlated with the simultaneous brain and tissue concentrations (r(2)>0.908, p<0.0001). On average, the brain levels were 6.3-13.1 and 5.4-17.6 times higher than the corresponding plasma level after oral and i.p. doses, respectively. The tissue to plasma level ratio of olanzapine was higher in other tissues. The data indicated that olanzapine is rapidly absorbed and widely distributed in the tissues of rats after oral and i.p. administration. The plasma concentration appears to predict the simultaneous concentration in brain and other tissues. There was no marked localized accumulation of olanzapine in any of the regions of the rat brain.     

Single dose safety, tolerance, and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent

1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of single and multiple ascending doses of the antiallergic agent tiacrilast in man

Five groups of six healthy subjects received single oral doses of 150, 300, 450, 600 or 750 mg tiacrilast 150 mg capsules, followed 24 h later by the same dose given every 6 h for 7 days, in a study designed to assess the pharmacokinetics of single and multiple doses of tiacrilast. Plasma samples were obtained at specified times after the initial dose, after 4 days of multiple dosing and after the last dose of tiacrilast. Samples were assayed for unchanged drug by a specific HPLC method. Wide variability was seen in the plasma concentration-time data. Plasma concentrations and pharmacokinetic parameters were nearly proportional to dose over the 150 to 750 mg dose range studied. Moreover, there was no evidence of unexpected accumulation of the drug in the plasma during multiple dosing and food did not appear to alter the bioavailability of tiacrilast to any clinically significant extent. The apparent elimination half-life was similar after single and multiple doses and ranged from 1 to 3 h.     

Pharmacokinetics of modified oral calcitonin product in healthy volunteers

STUDY OBJECTIVE: To assess the preliminary pharmacokinetics, pharmacodynamics, safety, and tolerability of single oral doses of a chemically modified salmon calcitonin product, CT-025, in healthy volunteers. DESIGN: Phase I, exploratory, five-way, open-label, nonrandomized, crossover study. SETTING: Clinical research center. SUBJECTS: Twelve healthy volunteers aged 22-44 years. INTERVENTION: A single oral dose of CT-025 was administered on 5 separate days with a 72-hour washout period between doses. Each dose consisted of CT-025 160 or 320 microg in varying relative concentrations of a mixture of excipients (formulations A, B, and C). MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected for determination of plasma CT-025, total serum calcium, and ionized serum calcium concentrations during the 4-hour period after dose administration. The data are the results from four of the five dosing days, when subjects received CT-025 in high and low concentrations of excipients. The data indicate that CT-025 was rapidly absorbed from the gastrointestinal tract. Mean peak plasma concentrations ranging from 51+/-51-110+/-59 pg/ml were observed 36-54 minutes after administration. Mean terminal elimination half-lives ranged from 54-76 minutes. There was a trend for the mean maximum concentration and area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable plasma concentration to increase with dose. Single oral doses of CT-025 160 and 320 microg were pharmacologically active, inducing a statistically significant decrease in total and ionized serum calcium concentrations. The rate of decrease in ionized serum calcium concentration was significantly related to the CT-025 dose. Single ora doses were well tolerated; some subjects experienced mild and transient nausea. CONCLUSION: Single doses of CT-025 were absorbed into the systemic circulation after oral administration and were well tolerated in healthy volunteers at doses up to 320 microg. These data suggest that oral delivery of salmon calcitonin becomes feasible with this product and support further clinical investigation of CT-025 as a treatment for osteoporosis and osteoporotic bone pain.     

Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency.

The pharmacokinetics and bioavailability of cyclobenzaprine, a widely used muscle relaxant, were investigated in four clinical studies, and the effects of age, gender, and hepatic insufficiency were characterized. Cyclobenzaprine plasma clearance was 689 ml/min, and the bioavailability of a 5 mg oral dose was 0.55. Following oral doses of 2.5 to 10 mg tid in healthy young subjects, cyclobenzaprine pharmacokinetics were linear, and plasma concentrations generally increased proportional to dose. There was about a fourfold accumulation of the drug in plasma on multiple dosing, corresponding to an effective half-life of 18 hours. Steady-state plasma concentrations of cyclobenzaprine in elderly subjects were twice as high as in young subjects following oral doses of 5 mg tid. Steady-state plasma concentration also appeared to be up to twofold higher in subjects with mild hepatic insufficiency compared to healthy controls. The magnitude of any difference in steady-state plasma concentration between males and females appears to be small relative to intersubject variability. A reduction in dose or dosing frequency should be considered in the elderly and in patients with liver disease.     

Distribution and elimination kinetics of carbamazepine in man

Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.Dedicated to the memory of Balzar Alexandersson, MD.Medical Research Council (U.K.) Travelling Fellow     

Effect of dose size on the pharmacokinetics of orally administered quinine

Plasma concentrations of quinine were measured by high-performance liquid chromatography (HPLC) after oral administration of 250, 500 and 1000 mg base to seven healthy adults. The doses were administered after an overnight fast. A washout period of at least 21 days was allowed between the doses. Area under the plasma concentration-time curve (AUC) for quinine increased in approximate proportion to the dose from 250 to 1000 mg. There was also a linear relationship between dose and maximum plasma concentration and dose and AUC in individual subjects. Time to reach peak plasma concentration remained unchanged over the dose range. There was no significant difference in elimination half-life, volume of distribution and systemic clearance over the dose range. The occurrence of adverse effects was dose and plasma quinine concentration dependent; central nervous system side effects increased as dose and plasma concentrations increased. These data suggest that after oral administration of quinine, linear pharmacokinetics occur in the dose range of 250–1000 mg.     

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.     

Dose- and time-dependent binding and kinetics of pindolol in patients with congestive heart failure

Dose- and time-dependent pharmacokinetics and plasma protein binding of pindolol were studied in patients with idiopathic cardiomyopathy who had mild to moderate congestive heart failure. The binding and plasma concentrations of pindolol at various times following the oral administration of single 5- and 10-mg doses and multiple 10-mg doses were determined. The binding of pindolol to plasma protein was time-dependent, increasing from 26% on the first day to 31% during the third day of treatment (P less than .05); this was probably due to increased alpha-1-acid glycoprotein concentration. Analysis of the plasma concentration-time data indicated dose-independent pharmacokinetics. Pindolol pharmacokinetics were time-dependent in one patient. Absorption and elimination half-lives ranged between 0.05 to 0.6 and 1.6 to 7.2 hours, respectively.     

Pharmacokinetics,brain distribution,and plasma protein binding of the antiepileptic drug lacosamide in rats

The study aimed to characterize the pharmacokinetics of lacosamide, a new antiepileptic drug, in rats after intravenous and oral administration at doses of 1, 3, 10, and 30 mg/kg. Moreover, brain distribution and plasma protein binding were estimated. After intravenous injection, terminal half-life, systemic clearance, and steady state volumes of distribution remained unaltered as a function of dose with values in the range 3.01–3.53 h, 221–241 mL/h/kg and 702–732 mL/kg, respectively. Following oral administration, absolute oral bioavailability was not dose dependent and was at 93.3–106%. However, the time to peak concentration and the dose-normalized peak concentration for 30 mg/kg were significantly different with those for other doses. The extent of urinary excretion of lacosamide was 17.1% and 16.5% for intravenous and oral doses, respectively, whereas fecal excretion was negligible. The brain to plasma ratio of lacosamide was consistent regardless of post-dosing time and the brain to plasma partition coefficient was 0.553. Further, the plasma protein binding of lacosamide was concentration independent with free fraction at 95.9%. Lacosamide showed linear pharmacokinetics at an intravenous dose of 1–30 mg/kg and an oral dose of 1–10 mg/kg but non-linear pharmacokinetics at a 30 mg/kg oral dose.     

Pharmacokinetics and oral bioavailability of carbimide in man

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.1, 0.3, 0.6, and 1 mg kg-1 and linear pharmacokinetics were observed for this dose range. Elimination half-life and total plasma clearance values ranged from 42 to 52 min and from 14.4 to 20.5 ml kg-1 min-1, respectively. After oral administration of 1 and 1.5 mg kg-1 of carbimide, elimination half-life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0.3 mg kg-1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10.5 to 15.5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0.3 and 1 mg kg-1 carbimide dose, respectively. The data indicate that there is a first-pass effect for carbimide.     

Pharmacokinetics of fluocortolone in long term therapy of patients with rheumatic and hematologic diseases

The pharmacokinetics of fluocortolone (Ultralan oral) and its effect on plasma cortisol levels were investigated during long-term treatment of patients with rheumatic and haematological diseases with different doses of fluocortolone. Fluocortolone was administered in the morning and plasma levels of fluocortolone and cortisol were measured in samples obtained 1.5, 3, 4, and 5 h p. adm. by means of specific radioimmunoassays. Maximum concentrations of fluocortolone in plasma (Cmax) and areas under the fluocortolone plasma level curves (AUC) increased linearly with the dose. The peak time (tmax = 2.04 +/- 0.85 h) and the plasma half-life (t1/2 = 1.53 +/- 0.52 h) were independent of the dose administered. Cortisol suppression as indicated by morning cortisol levels below 50 ng/ml plasma was not observed with doses below 10 mg/d.     

Pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats

This study reports the absorption, dose-linearity and pharmacokinetics of a novel antiangiogenic agent KR-31831 in rats after i.v. and oral administration at doses of 5, 10 and 25 mg/kg on both occasions. Concentrations of KR-31831 were determined by a validated LC/MS/MS assay method. After i.v. injection, plasma concentration-time profiles showed multi-compartmental characteristics, and there were no significant differences in Cl (20.8-27.7 ml/min/kg) and dose-normalized AUC (178.1-231 microg x min/ml based on the 5 mg/kg dose) as a function of dose. However, Vss was significantly increased at the 25 mg/kg dose (4931 ml/kg) compared with those (2288-2421 ml/kg) at lower doses. Subsequently, t1/2 was increased from 143-159 min at the lower doses to 304 min at the 25 mg/kg dose. The altered VSS was found to be a result of reduced plasma protein binding at relatively high concentrations. Following oral administration (doses 5-25 mg/kg), the absolute oral bioavailability ranged from 37.8% to 46.3%, and there were no significant alterations in dose-normalized AUC, Tmax, Cmax and t1/2 as a function of dose. The extent of urinary excretion was low for both i.v. (0.35%-0.54%) and oral (0.13%-0.33%) doses. Further discussions on the chemical and microsomal stability were included. In conclusion, dose-independent absorption kinetics were observed at oral doses from 5 to 25 mg/kg in rats. Orally administered KR-31831 could be eliminated mainly by the liver metabolic pathway.     

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.     

Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate

1 The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200  mg to 1600  mg were evaluated in healthy subjects.
2 Bismuth was only minimally absorbed (<0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33  ng  ml⁻¹ in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800  mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600  mg.
3 The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose-proportional and consistent with previous observations for ranitidine administered alone.
4 Ranitidine bismuth citrate was well-tolerated in single oral doses of up to 1600  mg.