Influence of cholestyramine on the pharmacokinetics of cerivastatin.

The possible influence of the bile acid sequestering agent cholestyramine, a basic comedication in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated. When both drugs were administered concomitantly in the morning under fasting conditions, a decrease in relative bioavailability by 21% could be observed, possibly due to irreversible adsorption of the statin to the resin. In addition, the delay in absorption led to a 41% decrease in cerivastatin mean maximum plasma concentration which also occurred at later time. A second study addressed in detail the question of time interval required between both treatments to minimize the influence of cholestyramine pretreatment on cerivastatin bioavailability: dosing of cerivastatin at dinner (6 p.m.) or bed time (10 p.m.) with cholestyramine pretreatment 1 hour before meal (5 p.m.) in both treatments. The decrease in mean AUC was now approximately 8-16% depending on the time of pretreatment (1-hour-interval: 16%, 5-hour-interval: 8%), and Cmax decreased by approximately 32%, irrespective of the time of pretreatment. Tmax was increased in both treatments, whereas t1/2 was not changed. The presented data support the conclusion that when administered concomitantly, the bioavailability of cerivastatin is moderately reduced by adsorption to cholestyramine. Following, however, the dosing instructions of both cholestyramine (1 hour before meal) and cerivastatin (once-daily in the evening at dinner or at bed time), i.e. administering both drugs several hours (at least 1 hour) apart, the observed effects on rate and extent of absorption of cerivastatin are unlikely to be of clinical relevance.

Concomitant administration of the alpha-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide.

OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. METHODS: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of glibenclamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. RESULTS: The concentration-time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUCnorm was 1.03 (geometric mean; 0.95-1.11, 90% confidence interval) and Cmax.norm 1.01 (0.94-1.08). The parameters were within the accepted range of 0.8-1.25 (AUC) or 0.7-1.43 (Cmax), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. CONCLUSIONS: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use.

The alpha-glucosidase inhibitor voglibose (AO-128) does not change pharmacodynamics or pharmacokinetics of warfarin.

OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases and is used for the treatment of diabetes mellitus. Since voglibose increases gastrointestinal motility and could thus affect absorption of concomitantly administered drugs, it was investigated whether or not voglibose modifies the pharmacodynamics and pharmacokinetics of warfarin, an oral anticoagulant frequently used in cardiovascular disorders likely to arise in diabetic patients. METHODS: Twelve healthy male subjects were given individually adjusted doses of warfarin to reduce prothrombin time (Quick's method) to a value of about 30-40% of the normal range within the first 8 days. Then, the individuals maintenance dose, given in the morning, was maintained until day 15. On study days 11-15, voglibose was co-administered per os in a dose of 5 mg t.i.d. The prothrombin time was determined on days 10 and 11 (reference) and on days 15 and 16 (test), and the steady-state pharmacokinetic characteristics of the warfarin enantiomers were determined on days 10 (reference) and 15 (test). The ratios test/reference were evaluated according to bioequivalence criteria. RESULTS: The equivalence ratio (test reference) for the pharmacodynamic parameter prothrombin time was 0.97 and for the pharmacokinetic characteristics AUC0-24 h.t.ss: S-(-)-warfarin, 1.05; R-(+)-warfarin, 1.01; and Cmax.ss: S-(-)-warfarin, 1.08; R-(+)-warfarin, 1.04. All parameters were within the predetermined accepted range of 0.7-1.43 (pharmacodynamics) or 0.8-1.25 (pharmacokinetics), thus fulfilling equivalence criteria. CONCLUSIONS: Voglibose modified neither the pharmacodynamics nor the pharmacokinetics of warfarin under steady-state conditions. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use.

Effect of buffering on pharmacokinetics of ketoprofen enantiomers in man.

AIMS: Concomitant administration of magnesium hydroxide may affect the rate or extent of absorption of non-steroidal anti-inflammatory drugs. In order to find out whether or not buffering modifies the pharmacokinetics of ketoprofen, plasma concentration-time courses resulting from oral administration of unbuffered formulations were compared with those of buffered formulations. METHODS: Two groups of 12 healthy and young male subjects were included in two randomized cross-over studies and received single oral doses of ketoprofen 12.5 or 25 mg, respectively, given as tablets which were either unbuffered or buffered with magnesium hydroxide/citrate. Ketoprofen enantiomers in plasma were determined by h.p. l.c. up to 24 h post-dose. RESULTS: Maximum plasma concentrations (Cmax) of both the (R)- and (S)-enantiomer, observed after administration of the buffered formulations (12.5 and 25 mg), were higher compared with the unbuffered tablets by about 50-80%. The area under concentration-time data (AUC) was unaffected, and, hence, Cmax/AUC was increased by buffering. Time to Cmax (tmax) and mean residence time (MRT) tended to be or was shortened by buffering. CONCLUSIONS: It is concluded that buffering of two ketoprofen formulations with magnesium hydroxide/citrate enhanced the concentration maximum by increasing the rate of absorption and leaving AUC unaffected.

Relative bioavailability of DL-oxyfedrine HCl after single-dose oral administration of tablets as compared to equimolar solutions.

The pharmacokinetics and comparative bioavailability of oxyfedrine after single-dose oral administration of oxyfedrine*HCl tablets in comparison to an equimolar aqueous solution of oxyfedrine*HCl were investigated in 12 healthy male subjects. Six of them received 96 mg DL-oxyfedrine*HCl as tablets and solution and the remaining 6 subjects received 16 mg DL-oxyfedrine*HCl as tablets and solution in a randomized cross-over design. For evaluation of the relative bioavailability of the tablet formulation, the main metabolite norephedrine (expressed as hydrochloride) was analyzed in plasma for all 12 subjects. Furthermore, for determination of the parent drug, samples of whole blood were analyzed for DL-oxyfedrine*HCl. Relevant concentrations of the parent drug were found only in the high dosage group. There was no evidence of dose-linearity referring to AUC and Cmax of norephedrine between 16-mg and 96-mg doses of DL-oxyfedrine*HCl. The relative bioavailability of the tablet formulation after administration of 16 mg DL-oxyfedrine*HCl, based on the metabolite norephedrine*HCl was for AUC: 85.37% within a 90% confidence interval of 69.29-105.17% and for Cmax: 78.79% within a 90% confidence interval of 59.19-104.90%. The figures for the 96 mg dose strength were: AUC: 107.85% (90.06-129.15%) and for Cmax: 74.74% (62.48-89.42%).

Pharmacokinetics and relative bioavailability after single dose administration of 25 mg ketoprofen solution as compared to tablets.

The relative bioavailability of ketoprofen from a liquid formulation as compared to a tablet formulation as reference after single oral dose administration was investigated in 16 healthy male subjects. The subjects received in a randomized, crossover design during one study period of 5 days 2.5 mg of ketoprofen as tablet or liquid formulation administered as single dose with a washout interval of 48 h. The plasma concentrations of S(+)- and R(-)-ketoprofen were determined before and up to 24 h post-administration. S(+)- and R(-)-ketoprofen in the collected plasma samples was determined using an internally standardized validated HPLC method. Regarding the geometric mean concentration-time courses there were no relevant differences between the two ketoprofen enantiomers for both formulations. Remarkable differences in the shape of concentration-time courses between the two formulations were found with higher Cmax (by about 70%) and earlier tmax (by 15 min) values for the ketoprofen solution. The treatments were widely equivalent with regard to AUC. The quotients of geometric means as well as 90% confidence intervals for AUC of R(-)-ketoprofen were 95.72% (92.55-99.00%) and for S(+)-ketoprofen 94.23% (89.91-98.76%). The administration of the ketoprofen solution resulted earlier in higher concentrations (by about 70%) for both enantiomers, whereas the extent of absorption expressed by AUC was nearly the same (about 95%) as compared to the equimolar tablet formulation. The differences between the two formulations for Cmax,norm and tmax were statistically significant.

Study on the absolute bioavailability of quinine and theophylline from tablets after single dose oral administration as compared to intravenous infusion in healthy male non-smoking volunteers.

This investigation was aimed at the determination of the absolute bioavailability of theophylline and quinine after single oral dose administration of Limptar tablets or Limptar N tablets with reference to intravenous administration of Euphyllin 0.48 short infusion and Chininum dihydrochloricum Buchler solution for injection. The study design was characterized as single dose, three-factorial, four-treatment, four-period Latin square design (factor A: period, factor B: treatment, factor C: sequence). The target parameters were AUCnorm, AUC0-infinity, ABA, and secondary parameters Cmax, tmax, t1/2 lambda z, MRT, HVD. The study was carried out on 12 healthy nonsmoking male volunteers between 24 and 42 years of age and confined to a ward for 4 study days (but not during the remaining days of washout phases which lasted 1 week). The treatments (not blinded) were as follows: b1, Chininum dihydrochloricum Buchler solution for injection, infusion of 163.3 mg quinine; b2, Euphyllin 0.48, short infusion of 168.6 mg theophylline; b3, Limptar tablets, 1 tablet containing 215.5 mg quinine and 167.2 mg theophylline; b4, Limptar N tablets, 1 tablet containing 165.75 mg quinine. A validated HPLC-UV method was used to determine plasma concentrations of drugs. The absolute bioavailability of theophylline and quinine from the two formulations Limptar and Limptar N was nearly complete (90% on the average). Administration of Limptar N tablets resulted in quinine concentrations which were higher and reached maximum faster as compared to administration of Limptar. Average quinine concentrations observed 8.0 h p.a. of Limptar exceeded those seen with Limptar N. Accordingly, this was as well reflected by a doubling of half duration time after Limptar compared to Limptar N. With respect to the safety parameters such as hemodynamics, ECG, hematology, clinical chemistry and urinalysis, there were no clinically relevant findings. All adverse events observed or reported during the study (mainly blurred vision and headache) were mildly pronounced, rated as possibly drug-related or unrelated to the study drugs, and disappeared spontaneously within the confinement period in the ward. In conclusion, the medications tested were well tolerated. No major differences in tolerability of quinine or theophylline given alone or in combination were observed. The difference in pharmacokinetic behavior of quinine in the two oral formulations may result from differences in pharmaceutical characteristics of the formulations.

Bioequivalence of two commercially available tamoxifen tablet formulations in healthy male volunteers.

Tamoxifen, a non-steroidal antiestrogen, is used in the palliative treatment of advanced breast cancer and as an adjuvant therapy after mastectomy. The bioequivalence of tamoxifen following single oral doses of Zemide 20 and a commercially available tablet formulation (reference formulation), each containing 30.4 mg tamoxifen dihydrogencitrate corresponding to 20 mg tamoxifen was investigated in 12 healthy male subjects. In a randomized, crossover study with a washout period of 13 weeks the volunteers received one pharmaceutical unit of both formulations after an overnight fast on an empty stomach. Plasma concentrations of tamoxifen were determined at predose and predetermined time points up to 20 days after administration using a validated HPLC method. The two tamoxifen formulations were proven to be bioequivalent for tamoxifen regarding rate and extent of absorption. The bioequivalence decision was based on Cmax, tmax and AUC0-t.

Pharmacokinetics and relative bioavailability of a new chewable, buffered acetylsalicylic acid tablet formulation in comparison to a conventional plain tablet.

The pharmacokinetics of acetylsalicylic acid (ASA) and its main metabolite salicylic acid (SA) following single dose administration of a new chewable, buffered ASA tablet formulation and a conventional plain ASA tablet formulation were investigated in 12 healthy male subjects. The volunteers received in a randomized, crossover design two pharmaceutical units of both formulations containing 500 mg ASA each after an overnight fast on an empty stomach. ASA and SA in the collected plasma and urine samples were determined using an internally standardized validated HPLC method. Regarding the normalized extent parameters for ASA, an increase of about 114% for the maximum concentration (Cmax,norm) and about 16% for the area under the curve (AUC0----infinity,norm) was found for the new chewable, buffered tablet formulation as compared to the plain tablet. Comparing the corresponding parameters for the main metabolite, both formulations were statistically equivalent. The quotient of normalized areas (QAUC0-20min, norm/AUC0----infinity,norm) for ASA was higher by about 124% for the new formulation, indicating an increased and faster absorption during the first 20 min after administration. The time of the concentration maximum did not differ statistically. These data indicate that the new chewable, buffered ASA tablet formulation shows a significant benefit as compared to the plain ASA tablet. The new tablet produced higher plasma ASA concentrations in a shorter time, which is clinically important since higher ASA concentrations are assumed to be related to an improved analgesic efficacy.

[Absolute bioavailability of a special sustained-release acetylsalicylic acid formulation]. / Absolute Bioverfügbarkeit einer speziellen, retardierten Acetylsalicylsäure-Zubereitung.

Absolute Bioavailability of a Special Acetylsalicylic Acid Sustained Release Formulation. The absolute bioavailability of an acetylsalicylic acid (ASA) sustained release formulation (Contrheuma retard), containing 300 mg ASA as initial dose and 350 mg in a retard formulation, was determined in comparison to a standard ASA solution for intravenous administration in a two-treatment, two-period cross-over trial with 6 healthy male volunteers by comparing the areas under the plasma-fluctuation-time curves of the primary metabolite. In addition, it was examined by comparison of the mean times after administration of both formulations, whether the test formulation meets the requirements of a sustained release formulation. The investigations led to the following results: The absolute bioavailability of the test formulation was 95%. The statistical comparison of the areas under the concentration-time courses allowed no decision (neither for equivalence nor difference). The maximal concentration of SA after intravenous administration of the standard formulation was reached after 0.4 h on an average and amounted to 62 micrograms/ml. After oral administration of the test formulation, a mean concentration maximum of 28 micrograms/ml was calculated, which had been reached after about 2 h. The differences are statistically significant. The mean time for SA was 6 h after the standard formulation, whereas after administration of the test compound, a mean of 11.5 h was calculated. 24 h following administration, the concentration of SA was 1.3 micrograms/ml after intravenous administration of the standard formulation and 5.5 micrograms/ml after administration of the test formulation. These differences, too, are statistically significant. From the comparison of the mean time for SA, a retard factor of 1.9 was calculated.

Internally standardized method for the determination of nalbuphine in human plasma by means of high performance liquid chromatography with electrochemical coulometric detection.

A high performance liquid chromatographic method with internal analogue standardization and electrochemical detection for the determination of nalbuphine in human plasma is described. Using 3 ml plasma the lower limit of detection is below 50 pg/ml, during the routine assay the limit of determination can be fixed at about 250-300 pg/ml. The calibration curve is linear in the range between 0.163-65 ng/l, the recovery rate from plasma exceeds 80%. The method was successfully applied in several pharmacokinetic studies.

[Elimination of nalbuphine in human milk]. / Elimination von Nalbuphin in die Muttermilch.

In order to examine the pharmacokinetics and excretion of nalbuphine (Nubain 20) in breast milk, patients suffering from postpartum pain were given a single dose of 20 mg nalbuphine intramuscularly. During a 24-h period, the total amount of nalbuphine excreted in the breast milk was 2.3 micrograms (mean value), which is equivalent to 0.012% of the dosage. The mean milk/plasma quotient was calculated using the AUC from the milk and plasma time curves at 1.2:1. An oral intake of 2.3 micrograms nalbuphine would not show any measurable plasma concentrations in the neonate. Adverse opioid reactions, e.g. respiratory depression are not to be expected even if one assumes a lack of glucuronide production in the neonate.

High-pressure liquid chromatographic method for the determination of hydromorphone in human plasma with electrochemical detection.

A high-pressure liquid chromatographic method with internal analogue standardization for the determination of hydromorphone (Dilaudid) in human plasma is described. The method involves extraction from plasma with chloroform and quantification with an electrochemical detector after high-pressure liquid chromatographic separation on an ion-pair column. Using 3 ml plasma the detection limit is about 50 pg/ml; in the routine procedure the limit of determination can be fixed at about 250 pg/ml with a correlation coefficient of about 10%. The method is selective. In case of extractions from blank plasma samples interfering peaks are not observed.

The effect of age on the pharmacokinetics of pentazocine.

Pentazocine was administered intravenously to 18 subjects, surgical patients and volunteers, ranging in age from 22 to 90 years. When divided into a young group (10 subjects, age 22-48 years) and an elderly group (8 subjects, age 60-90 years), the total clearance decreased as function of age from 22.14 +/- 4.114 to 11.68 +/- 3.593 ml/min/kg, and the elimination half-life increased from 2.5 +/- 0.71 to 4.11 +/- 1.187 hours. No change in the apparent volume of distribution was observed. Implications of change in clearance and half-life on dosage regimen design are discussed.

Theophylline-ranitidine drug interaction in the beagle dog.

Ranitidine (300 mg p.o.) and theophylline (15 mg/kg i.v.) were studied in Beagle dogs for possible drug interaction. Using a crossover design drugs were given alone and in combination. For the combination treatment ranitidine was given twice daily for two days before theophylline was administered. No significant differences in drug disposition were found for theophylline and ranitidine when given simultaneously. The mean total clearance of theophylline decreased in the presence of ranitidine by about 10%, and the mean total clearance of ranitidine decreased in the presence of theophylline by about 17%. Due to the small number of subjects, not more than a possible trend for reduction in total clearance was found. The total clearance in ml/min/kg for both ranitidine and theophylline is about 3 times higher in the Beagle dog than in man.

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.

Simple method for prediction and estimation of the hemodialysability of incorporated drugs.

This paper describes a simple method for measuring the hemodialysability of incorporated drugs, including mathematical equations. The method furnishes preliminary drug data in early phase I investigation. Relevance of the obtained results is shown by comparison with the established literature.

Pharmacokinetic studies with silymarin in human serum and bile.

Six subjects were given orally 560 mg of silymarin (silibinin 240 mg = 8 Legalon 70 dragees). The serum concentration curves and urinary excretion of silibinin, the principal constituent of silymarin, were measured. The maximum serum concentrations were low, ranging from 0.18 to 0.62 microgram/ml. The same was true of renal excretion, which amounted to only 1-2% of the silibinin dose over 24 hours. However, after giving 140 mg of silymarin (silibinin: 60 mg) to patients who had undergone cholecystectomy, bile collected from the T-tube drains was found to contain maximum silibinin concentrations of between 11 and 47 micrograms/ml. Though the dose was four times lower than in the previous experiments, these concentrations were approximately 100 times higher than in the serum. Because complete collection of bile from these patients was impossible and because it was not possible to collect individual samples in the time interval from 12-24 h, the conventional pharmacokinetic parameters required for bioavailability studies could not be calculated. However, computation of the value for AUC0-24 and for "mean time" (MT) provided data which enabled bioavailability comparisons to be made. A study in which the absorption of Legalon 35 and Legalon 70 dragees was compared provides an example for such bioavailability investigations in the bile.

Bioavailability of orally administered mesna.

The bioavailability of orally administered sodium 2-mercaptoethane sulfonate (mesna, Uromitexan drink ampoules) was tested in 18 healthy probands and in 5 tumor patients. Following single oral administration of 20 or 40 mg/kg mesna, 52.4% and 52.6%, respectively, of the dose were excreted in the urine as reactive thiol groups, the remainder as mesna disulfide (dimesna), the only metabolite of mesna; after i.v. injection of 20 mg/kg mesna, 48.7% of the dose administered appeared as thiol groups in the urine. Not until after 13.1 h (20 mg/kg p.o.) and 18.5 h (40 mg/kg p.o.), respectively, concentration drops below the minimum concentration of 100 micrograms/ml presumed to be still reliably protective. However, the elimination pattern and the time when the threshold concentration is reached are subject to marked individual variation. After i.v. administration of 20 mg/kg mesna and 9 times oral administration of 20 mg/kg mesna (the first dose concurrently with the i.v. injection, thereafter every 4 h), or 7 times oral administration of 20 mg/kg mesna (the first dose again concurrently with the i.v. injection, thereafter every 5 h), the percentage of the total dose administered appearing as thiol groups in the urine averaged 41.9% and 37.6%, respectively, up to 17 or 18 h after the last dose. Comparison of periods covering the same time of the day showed the total amount excreted to be higher on day 2 than on day 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Biperiden effects and plasma levels in volunteers.

The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accommodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).