Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.

The pharmacokinetics of pramiracetam was assessed using an HPLC method after oral administration of two different formulations of 600 mg (a solution and a tablet) of pramiracetam to 11 fasting volunteers. The mean kinetic parameters were: t1 = 4.7 +/- 2.4 - 4.3 +/- 2.2 h, AUC = 57.6 +/- 43.6 - 47.2 +/- 33.9 micrograms h/ml, Cmax = 6.80 +/- 3.2 - 5.80 +/- 3.3 micrograms/ml for the solution and the tablet respectively. The plasma profile of pramiracetam proved to be not highly affected by the formulation, only that the absorption rate was faster after oral administration of the drug in solution than after administration as a tablet. The half-life was very variable between subjects [2-8 hours], but less variable within subjects and it was unaffected by the formulation.     

Absolute bioavailability of moxonidine

In a randomized 2-way cross-over study with eighteen healthy male volunteers, two moxonidine preparations (tablets, treatment A vs. intravenous solution, treatment B) were tested to investigate absolute bioavailability and pharmacokinetics of moxonidine. The preparations were administered as single doses of 0.2 mg; prior to and up to 24 h after administration blood samples were collected and the plasma moxonidine concentrations determined. Urine samples were collected prior to and at scheduled intervals up to 24 h after administration for the determination of unchanged moxonidine. Moxonidine plasma and urine concentrations were determined by a validated gas chromatographic/mass spectrometric method with negative ion chemical ionization. The mean areas under the plasma concentration/time curves were calculated as [mean +/- standard deviation] 3438 +/- 962 pg.h/ml (AUC(0----Tlast)) and 3674 +/- 1009 pg.h/ml (AUC(0----infinity)) for treatment A; 3855 +/- 1157 pg.h/ml (AUC(0----Tlast)) and 4198 +/- 1205 pg.h/ml (AUC(0----infinity)) for treatment B. Mean peak plasma concentrations of 1495 +/- 646 pg/ml were attained at 0.56 +/- 0.28 h after oral treatment, mean peak plasma concentrations after intravenous treatment reached 3965 +/- 1342 pg/ml at 0.17 +/- 0.01 h (= coinciding with end of infusion). The mean terminal half-lives of moxonidine were derived as 1.98 h after administration of the tablet and as 2.18 h after infusion. The amounts of moxonidine excreted in urine during the 24 h following administration (Ae(24h)) in absolute figures and as percentage of the dose administered were 102 +/- 26 micrograms or 51 +/- 13% for the tablet and 122 +/- 33 micrograms or 61 +/- 16% for the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single dose absorption profiles and bioavailability of two different salbutamol tablets

In a single dose cross-over experiment in twelve healthy adults a comparison of the absorption profiles and the relative bioavailability was made between a new salbutamol containing tablet (preparation A = Salbutax) and a commercially available and accepted formulation as reference (preparation B), both containing 4 mg salbutamol. Salbutamol plasma concentrations were measured frequently during a period of 16 h post dosing. Maximum salbutamol plasma concentrations after intake of product A and product B on an empty stomach were reached after 2.3 +/- 0.9 (= mean +/- S.D.) and 2.4 +/- 1.1 h, respectively, and accounted for 14.3 +/- 2.5 and 12.8 +/- 2.6 micrograms X l-1, respectively. The differences were not found to be significant (p greater than 0.05). The areas under the plasma concentration-time curves (AUC0----16), as obtained after administration of tablet A and tablet B, accounted for 73.5 +/- 14.0 and 65.0 +/- 11.8 micrograms X l-1 X h, respectively, the difference being marginally significant (p = 0.05). This results in a relative bioavailability of 114.3 +/- 15.7% for the product A 4-mg tablets. It is concluded that both products can be considered as having comparable bioavailability.     

Lack of correlation between lithium pharmacokinetic parameters obtained from plasma and saliva

One tablet containing 755 mg of lithium tryptophanate (10.8 mEq of lithium) was administered to eight healthy volunteers. The main pharmacokinetic parameters for the group of subjects were estimated. Pharmacokinetic parameters (mean +/- SD) from plasma and saliva were respectively: half life (t1/2) 17 +/- 6 vs. 21.8 +/- 14 h; mean residence time 23.7 +/- 7.4 vs. 24.4 +/- 15.3 h; total clearance 30.6 +/- 9.3 vs. 28.6 +/- 6.2 ml/h/kg; and apparent volume of distribution 0.71 +/- 0.20 vs. 0.84 +/- 0.37 L/kg. Although the mean pharmacokinetic parameters in plasma and saliva were similar, there was no significant correlation between the calculated parameters in the individual subject (p greater than 0.05). The usefulness of monitoring salivary levels of lithium is questionable.     

Plasma pharmacokinetics of cinmetacin following oral administration in healthy volunteers

The pharmacokinetics of a single 600 mg oral dose of 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid (cinmetacin, Cindomet) was studied in 8 healthy volunteers of both sexes. Plasma levels of the drug were assayed by using an HPLC technique ad hoc devised. Following administration, the Cmax was reached at the 2nd h in 7 out of 8 subjects with an average value of 18.19 micrograms/ml; 12 h after the dose (last sampling time) appreciable plasma levels of cinmetacin were measured, corresponding to 17.2% of the maximum average concentration. The mean values +/- S.E. concerning the elimination half-life, the total volume of distribution, the total plasma clearance and the total area under the curve were 3.80 +/- 0.21 h, 0.28 +/- 0.03 l/kg, 0.051 +/- 0.005 l/kg/h, and 125.64 +/- 15.97 micrograms.h/ml, respectively. The plasma decay of cinmetacin was monophasic and the data were interpreted according to a one-compartment open model. Overall results indicate that cinmetacin is well and rapidly absorbed orally and widely distributed in body fluids.     

Comparison of pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly and young subjects.

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Comparative biological availability of two different ibuprofen granules]

Bioavailability of ibuprofen (CAS 15687-27-1) was investigated in 12 healthy volunteers who received 2 sachets of newly developed effervescent granules (Imbun), each containing 500 mg of ibuprofen lysine salt (corresponding to 292.6 mg of ibuprofen) as the test preparation and 1 sachet of commercially available granules containing 600 mg ibuprofen. Blood samples were withdrawn pre-dose and at 16 occasions until 10 h post dose. Ibuprofen plasma concentrations were assayed by HPLC using a proprietary column-switching technique. Maximum plasma concentrations, Cmax, and times of their occurrence, tmax, were taken from the plasma data directly, areas under the plasma level/time curves, AUC0-10, were calculated using the trapezoidal rule. Pharmacokinetic parameters were checked for significant differences using ANOVA with p = 0.05. When the test preparation was applied maximum ibuprofen levels of 60 +/- 17 micrograms/ml were reached at 27 +/- 17 min p. appl. while Cmax was 52 +/- 12 micrograms/ml at tmax = 94 +/- 27 min after application of the reference preparation. AUC values were 150 +/- 44 microgramsh/ml (test) and 148 +/- 33 microgramsh/ml (reference), respectively. Thus, relative bioavailability of ibuprofen was 101.8 +/- 16.3% (or 104.1 +/- 16.7% when the slight differences in doses were corrected for). Differences in extent of absorption as measured by AUC and Cmax proved to be insignificant whereas differences in absorption rate as measured by tmax were highly significant (p < 0.001).     

A new trifluorinated quinolone: Ro 23-6240 (AM 833)

Ro 23-6240 is a new fluoroquinolone displaying pronounced activity against a wide range of Gram-positive and Gram-negative pathogens. In order to obtain information about the absorption, distribution and excretion of this quinolone in man, six healthy volunteers received in cross-over an intravenous infusion of 100 mg Ro 23-6240 and an oral dose of two tablets corresponding to 400 mg Ro 23-6240. Serial plasma and urine samples were assayed for unchanged substance by HPLC with subsequent fluorescence or UV detection. Pharmacokinetics were evaluated from these data assuming a two-compartment open model. Characteristic of this new antibacterial are the high plasma levels following oral administration (Cmax: 4.5 micrograms/ml) and the long elimination half-lives (8-12 h). Both these parameters are favourable kinetic prerequisites for a once-a-day dosage regimen. In addition, the volume of distribution at steady state clearly exceeds 1 l/kg and points to good tissue penetration. Total systemic clearance was 122 ml/min and total renal clearance reached 89 ml/min. Within 96 h, 60-70% of the administered dose was recovered from urine as unchanged drug. The absolute bioavailability (extent of absorption) of the tablet amounted to 96%, indicating a complete absorption of this galenic formulation.     

Pharmacokinetics of nifedipine derived from a new retard tablet formulation

A nifedipine retard tablet formation (Glopir, 20mg) was developed to reduce the number of daily doses required in the treatment of hypertension. The plasma pharmacokinetics of this oral formulation were examined, in a single study, on 12 healthy volunteers. Single 20 mg doses of nifedipine retard tablet (Glopir, GAP & Co. Athens, Greece) were given after an overnight fast and 10 blood samples were drawn during the first 24 h after administration. Plasma concentrations of nifedipine were measured by high performance liquid chromatography. The mean peak plasma nifedipine concentration was 27.6 ng/ml at a maximum time of 24 h, after tablet ingestion. The mean apparent nifedipine elimination half-life was 16.0 +/- 7.5 h and the mean area under the plasma concentration time curve (0-24 h) 404.1 +/- 134.0 ng/ml.h. The data suggest that the tablet form has properties of a sustained-release preparation, with slow accumulation and elimination phases and can appropriately be given in a twice-daily regimen.     

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.     

Is epinephrine administration by sublingual tablet feasible for the first‐aid treatment of anaphylaxis? A proof‐of‐concept study

PURPOSE: In order to explore the feasibility of sublingual administration of epinephrine tablets as a non-invasive first-aid treatment for anaphylaxis, we studied epinephrine absorption from this dosage form in an animal model. METHODS: In a prospective, randomized, four-way crossover study, six rabbits received epinephrine 2.5 or 10 mg as a sublingual tablet, epinephrine 0.03 mg (0.3 ml) by intramuscular (IM) injection (positive control), and 0.9% NaCl (0.3 ml) IM (negative control). Pre- and post-dose blood samples were obtained for measurement of plasma epinephrine concentrations by HPLC-EC. RESULTS: After administration of epinephrine 2.5 mg as a sublingual tablet, the mean (+/-SEM) C(max) was 2369+/-392 pg/ml, and the t(max) was 20.8+/-5.7 min. After administration of epinephrine 10 mg sublingually, the C(max) was 10836+/-2234 pg/ml, and the t(max) was 21.7+/-5.4 min. After IM epinephrine, the C(max) was 6445+/-4233 pg/ml, and the t(max) was 15.8+/-4.7 min. After IM 0.9% NaCl, the C(max) (endogenous epinephrine) was 518+/-142 pg/ml. The t(max) after both of the sublingual epinephrine tablet doses did not differ significantly from the t(max) after IM epinephrine, and the C(max) after the 10 mg sublingual epinephrine tablet dose did not differ significantly from the C(max) after IM epinephrine. CONCLUSIONS: In this proof-of-concept study, administration of epinephrine as a sublingual tablet formulation resulted in rapid achievement of peak plasma epinephrine concentrations. Absorption studies in humans are needed. DEFINITIONS: HPLC-high performance liquid chromatography; EC - electrochemical detection; C(max) - maximum plasma epinephrine concentration after dosing; t(max) - time of maximum plasma epinephrine concentration.     

Pharmacokinetics and bioequivalence of different formulations of pirenzepine

An intraindividual comparative single-dose study was carried out under carefully controlled conditions on 12 healthy volunteers in order to establish the bioavailability of 5,11-dihydro-11-[(4-methyl-piperazin-1- -yl)acetyl]-6H-pyrido[2,3b][1,4]benzodiazepin-6-one dihydrochloride (pirenzepine), the active principle of newly developed tablets (Gastricur) and suspension containing 10 mg. In an additional multiple dose, cross-over study on 12 healthy volunteers, the bioequivalence of pirenzepine was investigated after administration of the newly developed vs. commercial dose-equivalent tablets. Pirenzepine was assayed from plasma by a new, highly sensitive high-performance liquid chromatography method. A 3-compartment model was taken as a basis for the calculation of the plasma concentration curves and the pharmacokinetic parameters. Following i.v. administration, the terminal elimination half-life, t 1/2, the volume of distribution, V1, and the total plasma clearance Cl were determined to be 7.7 +/- 1.4 h, 0.255 +/- 0.057 l/kg and 263.4 +/- 56.8 ml/min, respectively. From the tablet and suspension formulation the systemic availabilities were calculated to be 33.5% and 20.3%, respectively. In the multiple dose study, both tablet forms investigated were bioequivalent.     

Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers

The bioavailability of drotaverine (CAS 14009-24-6) was investigated after oral administration of a drotaverine capsule preparation (20 mg Droxa mite) and compared to that of a reference tablet preparation. The preparations were investigated in 23 healthy volunteers, aged between 20 and 27 years, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of drotaverine plasma concentrations were collected at pre-defined time points up to 30 h following drug administration. A washout period of two weeks separated both treatment periods. Drotaverine plasma concentrations were determined by means of a validated HPLC method (UV detector, imipramine HCl salt as an internal standard). The limit of detection was 6 ng/ml. Values of 1593.92 +/- 949.70 ng x h/l (95% confidence interval (CI): 1183.20-2004.60) for the test and 1705.48 +/- 737.78 ng x h/l (95% CI: 1386.40-2024.50) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax of 121.89 +/- 37.03 ng/ml (95% CI: 104.05-139.80) and 121.85 +/- 37.97 ng/ml (95% CI: 107.09-135.74) and time to reach maximum plasma concentration--Tmax of 1.29 +/- 0.42 h (95% CI: 1.11-1.48) and 1.14 +/- 0.34 h (95% CI: 0.99-1.29) achieved for the test and reference preparations did not differ significantly. The relative bioavailability (AUC(0-infinity) ratio test/reference) and Cmax ratio test/reference were 103.15% (90% CI: 81.68-124.60) and 103.74% (90% CI: 94.10-113.38), respectively. AUC was calculated using two different methods. There were no significant differences between the obtained values. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the European Agency for the Evalution of Medicinal Products (CPMP) and the Food and Drug Administration, it is concluded that the new drotaverine capsule formulation is therapeutically equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.     

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose

Chlormezanone plasma concentrations were determined in 5 volunteers (group 1) after a single oral dose of 200 mg of chlormezanone with high performance liquid chromatography. A plasma elimination half-life of 23 +/- 2.3 h was calculated. The mean peak chlormezanone plasma level was 1.86 +/- 0.2 micrograms/ml, 1 h after ingestion. Additionally, chlormezanone plasma levels were determined after repeated oral doses of chlormezanone recommended for treatment of muscular spasms due to degenerative skeletal disease. After 5 days of repeated daily doses of 3 x 200 mg (group 2; 12 patients) or 3 x 400 mg (group 3; 10 patients) of chlormezanone, mean predose chlormezanone plasma levels were 12.0 +/- 2.0 micrograms/ml (group 2) and 22.7 +/- 4.0 micrograms/ml (group 3), respectively. Comparable plasma concentrations were determined after 10 days of repeated doses of 3 x 200 mg or 3 x 400 mg of chlormezanone in 3 patients from each of these 2 groups. In 7 patients of group 3, chlormezanone had to be discontinued on the 5th day due to increasing muscular weakness, ataxia and exercise-inducible tachycardia. After a loading dose of 800 mg and repeated doses of 3 x 200 mg chlormezanone to 5 patients (group 4), plasma levels of 6.5 +/- 2.1 micrograms/ml, 8.9 +/- 2.2 micrograms/ml, 12.7 +/- 2.0 micrograms/ml, and 10.4 +/- 2.4 micrograms/ml were determined after 2, 8, 16, and 36 h, respectively. Trace amounts of a degradation product of the acid-labile chlormezanone could be detected in plasma besides the unchanged drug after administration of repeated oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations of theophylline and quinine in healthy volunteers following oral administration of a fixed drug combination

Theophylline and quinine plasma concentrations were determined in 4 healthy volunteers following oral administration of two tablets of Limptar . According to the recommended dose schedule the second tablet was administered 3 h after the first tablet. Peak concentrations of theophylline and quinine in the plasma were observed at 5.4 h (theophylline) and 5.1 h (quinine), respectively, following administration of the first tablet. Half-life of theophylline ranged from 7.2 to 15.4 h (9.4 +/- 4.4 h; mean +/- SD) and that of quinine from 5.4 to 27.2 h (14.4 +/- 9.2 h). Peak concentrations of theophylline in the plasma (7.5 +/- 1.6 micrograms/ml) are below those which are thought to produce concentration-dependent side effects. Besides the superior therapeutic efficacy of the combination of quinine and theophylline compared to that of quinine alone, this combination seems to be favourable also from a pharmacokinetic point of view.     

Pharmacokinetics of triflusal and its main metabolite in rats and dogs.

The methods for determining plasma concentrations of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) that have been described, do not distinguish between the drug and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid). In the present study, we have developed a new analytical technique based on HPLC that enabled us to carry out a pharmacokinetic study of the drug and its metabolite in animals. An intravenous or oral dose of 50 mg/kg was administered to male Sprague-Dawley rats, and 15 mg/kg was administered to beagle dogs. Plasma levels of triflusal and HTB were determined. In rats, triflusal was quickly eliminated from plasma with a biological half-life (t1/2) of 2.7 min and a clearance (Cl) of 73.4 (ml/kg)/min. The elimination of HTB was much slower with a t1/2 of 21.5 h and a Cl of 5.1 (mg/kg)/h. The maximum concentration (Cmax) of triflusal in rats after an oral administration was 8.1 +/- 2.0 micrograms/ml reached between 2.5 and 10 min. The Cmax of HTB was 237.7 micrograms/ml and was achieved at 0.7 h. The bioavailability of triflusal in rats was only 10.6% while the bioavailability of HTB was more than 100% indicating an important first pass effect. In dogs the t1/2 of triflusal was 14.4 +/- 5.9 min and the Cl was 25.1 +/- 4.7 (ml/kg)/min. HTB was also eliminated very slowly with a t1/2 of 71.1 +/- 12.5 h and a Cl of 2.4 +/- 0.3 (ml/kg)/h. The Cmax of triflusal in dogs was 13.3 +/- 2.9 micrograms/ml and was reached after 19.2 +/- 6.1 min (tmax).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of pirazolac, a new anti-inflammatory drug, in human volunteers. III. Steady state plasma levels

Seven male, young subjects received twice daily 300 mg of pirazolac (PAA) for one week and twice daily 600 mg PAA for a further week as tablet. Plasma levels of PAA were monitored every day just before dosing and up to 72 hours after the last dose using a specific HPLC-method. During the first week of treatment trough steady state levels of Cssmin = 24 +/- 8 micrograms/ml were reached at day 4. After changing of dose regimen to twice daily 600 mg a new steady was established four days later with Cssmin = 62 +/- 15 micrograms/ml. PAA in the plasma was highly (99.2 +/- 0.8%) bound to plasma proteins. Time course of the decay of PAA levels in the plasma after the last dose was similar to that after a single administration.     

Spline functions in convolutional modeling of verapamil bioavailability and bioequivalence. II: study in healthy volunteers.

The pharmacokinetics of a new verapamil retard tablet formulation have been investigated in a randomized cross-over bioequivalence study on 12 healthy subjects. The drug was given orally at a single new or standard retard tablet dose of 240mg and at a single intravenous dose of 5mg. Plasma verapamil concentrations were determined by HPLC. New retard tablets produced peak plasma verapamil concentrations of 81.34+/-5.69microg/l, time to peak plasma concentrations of 4.91+/-0.89h and an AUC (0-24h) of 1291+/-103.4h x microg/l, with a terminal phase half-life of 55.1+/-14.9h. After intravenous administration verapamil exhibited biphasic elimination kinetics with a terminal plasma half-life of 2.36+/-0.42h and systemic clearance of 34.32+/-5.81 l/h. Bioavailability of the new peroral retard formulation ranged from 19.49+/-4.41% to 67.69+/-11.70%. Absorption rates and amounts were evaluated by means of the spline-convolutional method. Input rates for the new verapamil retard formulation ranged from 0.77+/-0.20mg/h to 5.57+/-1.58mg/h. The cumulative amount of verapamil input was 39.17+/-9.71% for the new retard tablets. All pharmacokinetic parameters for the new verapamil retard tablet formulation, were in reasonable agreement with the data obtained on already registered verapamil retard formulations, indicating their bioequivalence.