Pharmacokinetics and metabolism of zamifenacin in mouse, rat, dog and man.

1. Zamifenacin was rapidly metabolized in vitro by liver microsomes from rat, dog, and man. 2. Zamifenacin exhibited extensive plasma protein binding with human plasma showing 20 and 10-fold higher binding that that in rat and dog respectively. 3. Following oral administration to animals, metabolic clearance resulted in decreased bioavailability due to first-pass metabolism in rat and mouse. Oral clearance in man was low as a result of increased metabolic stability and increased plasma protein binding compared with animals. 4. Metabolism was the major route of clearance of zamifenacin with the primary metabolic step resulting in opening of the methylenedioxy ring to yield the catechol. In man, this metabolite was excreted as the glucuronide conjugate, whereas in the animal species it was further metabolized by mono-methylation of the catechol.

Absence of a sertraline-mediated effect on digoxin pharmacokinetics and electrocardiographic findings.

UNLABELLED: The effects of oral administration of sertraline on the plasma concentration profile and renal clearance of digoxin were assessed in 20 healthy male subjects in a double-blind, randomized study. METHOD: All subjects first received digoxin 0.5 mg twice daily on Day 1, 0.25 mg twice daily on Day 2, and 0.25 mg daily thereafter. On Day 11, 10 subjects began concomitant sertraline administration with an initial dose of 50 mg/day that was titrated upward over 7 days to 200 mg/day, which was given over the remainder of the study period. The other 10 subjects received concomitant digoxin and placebo for 17 days beginning on Day 11. Trough plasma concentrations of digoxin were monitored daily beginning on Day 7. Blood samples and 24-hour urine collections were used to determine steady-state digoxin concentration and renal clearance before, during, and after sertraline coadministration. RESULTS: Sertraline had no effect on digoxin pharmacokinetics, except for a decrease in the time to reach the maximum plasma digoxin concentration (Tmax) compared with placebo (p = .0046), a finding thought to be of limited clinical significance. Side effects of mild-to-moderate severity were reported by 5 of 10 sertraline-treated subjects and by 6 of 10 placebo-treated subjects. CONCLUSION: The results of this study suggest that dosing adjustments of digoxin may not be necessary in patients receiving concomitant sertraline administration.

Pharmacokinetics of tenidap sodium administered with food or antacid in healthy volunteers.

1. The effects of food and antacid on the pharmacokinetics of tenidap were investigated in this randomised, 3-way cross-over study. 2. Twenty-one healthy young men, mean age 27.4 years, received single oral doses of tenidap sodium 120 mg at weekly intervals after either an overnight fast, with food or with 20 ml of the antacid Maalox (aluminum hydroxide 1.8 g and magnesium hydroxide 1.2 g). Plasma samples collected immediately before and up to 96 h after each tenidap dose were assayed for tenidap using a validated h.p.l.c. method. The assay data were used to determine the pharmacokinetic parameters of tenidap in each group. 3. Co-administration of tenidap with food produced a statistically significant delay in the rate of absorption (tmax, 4.4 h) (P < 0.001). There was no statistically significant change in Cmax. However, co-administration with the antacid significantly decreased both the mean rate and extent of absorption of tenidap compared with the fasting state: AUC, 420.93 micrograms ml-1 h (antacid), 476.31 micrograms ml-1 h (fasting) (P = 0.026); Cmax 14.3 micrograms ml-1 (antacid), 18.0 micrograms ml-1 (fasting) (P = 0.001); tmax 4.5 h (antacid), 2.9 h (fasting) (P < 0.001). Neither food nor the antacid had any effect on the elimination of tenidap. These changes in tmax are unlikely to be of any clinical significance owing to the long half-life of tenidap. 4. Treatment was well tolerated. Only two adverse events were reported that were considered by the investigator to be related to tenidap. There were no reports of laboratory or cardiovascular abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of tenidap sodium on digoxin pharmacokinetics in healthy young men.

1. The effects of tenidap sodium and placebo on digoxin pharmacokinetics were compared in 14 healthy young men, in a double-blind, parallel-group study lasting for 24 days. 2. Subjects were administered digoxin alone for the first 10 days and digoxin plus tenidap 120 mg day-1 or placebo for the remaining 14 days. 3. Changes in the means between day 10 (digoxin monotherapy) and day 24 (combined therapy) for renal clearance, area under the plasma concentration-time curve during the dosing interval, and the minimum and maximum plasma digoxin concentrations did not differ significantly between the tenidap and placebo groups. There was a small but statistically significant increase (0.5 h) in the time taken to reach maximum plasma digoxin concentration following 14 days' continuous tenidap co-administration compared with placebo, but this was not considered to be clinically meaningful. 4. Co-administration of tenidap and digoxin was well tolerated. No subject withdrew from the study during combination treatment. Treatment-related adverse events were of mild to moderate severity and were reported by four subjects on digoxin monotherapy, four on tenidap and digoxin, and by two on digoxin and placebo. Those reported by the tenidap group predominantly affected the gastrointestinal system and were mild in severity. There were no reports of laboratory test abnormalities or cardiovascular abnormalities related to combined digoxin and tenidap administration. 5. The results of this study indicate that, in healthy young men, co-administration of tenidap with digoxin does not have any apparent clinically significant effects on the pharmacokinetic profile of digoxin, and the treatment is well tolerated.

An investigation into the effect of tenidap sodium on the pharmacokinetics of a combined oral contraceptive.

1. The effects of tenidap sodium and placebo on the pharmacokinetics of a combined oral contraceptive (Microgynon 30) were evaluated in 18 healthy premenopausal women in a double-blind, cross-over study lasting two menstrual cycles. 2. Tenidap (120 mg day-1) or placebo was given for 11 days, starting within 4 days of menstruation and Microgynon 30, containing levonorgestrel (150 micrograms) and ethinyloestradiol (30 micrograms), was administered on day 10 of tenidap therapy. 3. The mean maximum plasma levonorgestrel concentrations (Cmax), time to Cmax (tmax) and area under the plasma time-concentration curves (AUC(0,t)) did not differ between subjects given tenidap or placebo. The Cmax, tmax and AUC(0,t) values for ethinyloestradiol did not differ between tenidap and placebo recipients. Only the ethinyloestradiol Cmax showed a significant difference (P = 0.02) between menstrual cycles 1 and 2 (252.9 pg ml-1 and 271.3 pg ml-1, respectively). 4. Co-administration of tenidap and Microgynon 30 was well tolerated and no subject withdrew from the study because of side-effects. There were no side-effects considered to be related to tenidap and no clinically significant laboratory abnormalities were considered to be related to treatment. 5. The results of the study suggest that the pharmacokinetics of the oestrogen and progestin components of the oral contraceptive Microgynon 30 are unlikely to be affected by concomitant administration of tenidap.

PIP: In Belgium, clinicians enrolled 18 healthy premenopausal women attending the St. Remi Clinic in Brussels in a double-blind, cross-over study lasting two menstrual cycles to examine the effect of the new anti-rheumatic drug, tenidap sodium, on the pharmacokinetics of a combined oral contraceptive (OC) containing 150 mcg levonorgestrel and 30 mcg ethinyl estradiol. Beginning with the fourth day of menstruation, the women received either an oral dose of three 40 mg capsules or a matched placebo once a day over 11 days during the first menstrual cycle. During the second cycle, they received the treatment that they did not receive during the first cycle. Regardless of cycle, they received the OC (Microgynon 30) on day 10 of tenidap therapy. There was no appreciable difference in mean maximum plasma levonorgestrel concentrations (Cmax), time to Cmax (tmax), and area under the plasma time-concentration curves (AUC[0,t]) between the tenidap group and the placebo group. The same was true for ethinyl estradiol. In the tenidap group, however, the ethinyl estradiol Cmax increased significantly between menstrual cycles 1 and 2 (252.9-271.3 pg/ml; p = 0.02). No tenidap-related side effects occurred. Five women reported menstrual irregularities, which were attributed to the single dose of OCs. No one experienced significant changes in heart rate or blood pressure. These findings show no pharmacokinetic interaction in women receiving tenidap and the OC simultaneously. Thus, tenidap use should not reduce OC efficacy.

Pharmacokinetics of fluconazole in pediatric patients.

The pharmacokinetic properties of fluconazole were studied in more than 100 pediatric patients, including 12 premature neonates. The volume of distribution and the rate of elimination differed significantly from the values reported for adults. The volume of distribution varied with age, being greatest during the neonatal period (1.18 to 2.25 l/kg) and decreasing by young adulthood to a value similar to that reported for adults (0.7 l/kg). With the exception of neonates, fluconazole clearance was generally more rapid in children than in adults, with a mean plasma elimination half-life of just over 20 h for all pediatric age groups. In neonates, fluconazole was eliminated slowly, with a mean elimination half-life of 88.6 h at birth, 67.5 h approximately one week later and 55.2 approximately two weeks after birth. Fluconazole appeared to be well absorbed from the gastrointestinal tract. These pharmacokinetic results, taken in conjunction with the corresponding data for adults, provide a sound basis for establishing appropriate fluconazole dosage recommendations for pediatric patients.

Pharmacokinetics of theophylline and its metabolites during acute renal failure. A case report.

After unsuccessful therapy with salbutamol syrup and inhaled terbutaline a 3-year-old boy with an acute exacerbation of asthma was treated with nebulised salbutamol (albuterol), intravenous aminophylline and hydrocortisone. His condition continued to deteriorate and he required artificial ventilation. Subsequently, he became anuric, with liver dysfunction, nonspecific encephalopathy and limb tremor. Peritoneal dialysis was started. Plasma theophylline concentrations were monitored and maintained in the therapeutic or subtherapeutic range. Despite this, he was hyper-reflexic with limb tremor. Excessively high plasma concentrations of the principal theophylline metabolite, 1,3-dimethyluric acid, were found [maximum 92 mg/L (470 mumol/L)], which cleared only with the return of normal renal function. Plasma concentration monitoring of drugs other than theophylline was not performed. After the patient recovered, a pharmacokinetic study demonstrated that normal methylxanthine metabolism was re-established. Pharmacokinetic analysis indicated that the undue accumulation of the metabolites was a result of an inability to clear these compounds. Thus, pharmacologically and toxicologically active metabolites of theophylline may accumulate in anuric patients on peritoneal dialysis, producing clinical symptoms of toxicity. However, in the present case the possible role of metabolites of other drugs cannot be definitely excluded.

Age and the pharmacokinetics of morphine.

Eight healthy young and nine healthy elderly volunteers received 10 mg morphine sulphate as an intravenous infusion, an oral solution and a slow-release tablet (MST Continus, Napp Laboratories) on three separate occasions. Pharmacokinetic profiles of morphine base were measured over a 24-h period using 13 sampling times. The elderly group showed decreased morphine clearance with a trend to a smaller volume of distribution. They achieved higher maximum plasma concentrations (Cmax) after both oral formulations and had larger areas under the plasma concentration-time curves. The times to reach maximum concentrations were the same in both groups for all formulations.

On the absorption of clavulanic acid.

It was not possible to computer fit oral clavulanic acid data using exponential or model equations incorporating a single exponential defining the absorption phase. Using the Loo-Riegelman method three phases of the absorption process became apparent, an initial slow phase, a more rapid phase and a final slow phase, contributing approximately 20, 70, and 5%, respectively, to the overall absorption process. Statistical moment analysis of clavulanic acid data following intravenous and oral solution administration gave mean values for the mean residence time, mean absorption time, and volume of distribution steady-state of 56 min, 43 min, and 14.01, respectively. Weibull analysis of the oral solution data gave mean values for lag-time and mean absorption time of 8 min and 46.8 min, respectively. Administration of clavulanic acid in a capsule formulation increased the lag-time before absorption but had no significant effect on the mean absorption time.

Pharmacokinetics of parenteral ticarcillin formulated with clavulanic acid: Timentin.

The pharmacokinetics of a formulation of clavulanate potentiated ticarcillin (Timentin) have been investigated following a bolus intravenous injection of 1.2 g, infusions of 3.2 g over periods ranging from 30 minutes to three hours, and a bolus dose of 1.2 g followed by an infusion of 3.2 g. The effect of probenecid has also been investigated. The serum levels of clavulanic acid are discussed in relation to the microbiology and therapeutic implications.

Bioavailability and pharmacokinetics of clavulanic acid in healthy subjects.

The bioavailability and pharmacokinetics of clavulanic acid were studied following oral solution and rapid intravenous administration to healthy volunteers. Plasma and urine samples were collected at frequent intervals following dose administration and were assayed for clavulanic acid by an enzyme inhibition method. Plasma data after intravenous administration were subjected to pharmacokinetic analysis using a two-compartment open model. The mean absolute bioavailability of clavulanic acid from oral solution was 0.75, derived from both urine and plasma data. No changes in the disposition pharmacokinetics of clavulanic acid with route were found, with a mean renal clearance of 0.1051 X min-1 and mean terminal elimination rate constant of 0.0134 min-1.

High-performance liquid chromatographic analysis of amiloride in plasma and urine.

A high-performance liquid chromatographic method has been developed for amiloride in rabbit plasma and urine which uses a reversed-phase C18 column, a mobile phase (flow-rate 2 ml/min) consisting of 32% acetonitrile in 0.15 M perchloric acid, pH 2.2, and spectrofluorometric detection via excitation at 286 nm. A simple extraction step with ethyl acetate eliminates interfering peaks. Short retention times of about 2.3 and 3.8 min are observed for amiloride and the internal standard, triamterene, respectively. The method can measure 4 ng/ml amiloride in plasma. This assay has been used to explore the pharmacokinetics of amiloride in rabbits. The plasma disposition profile is biexponential after a 50-mg intravenous bolus dose and there is no evidence for saturable elimination at zero-order infusion rates of 1.8, 3.6 and 7.2 mg/h.

Stability and sterility of cimetidine admixtures frozen in minibags.

The stability and sterility of cimetidine hydrochloride admixtures after freezing for extended periods were investigated. Cimetidine hydrochloride, 300 mg, was added to each of six 50-ml minibags containing 5% dextrose injection. The cimetidine concentration was determined and the bags were frozen for up to 30 days. After freezing for the appropriate length of time, the bags were thawed. Cimetidine concentrations were determined by high-pressure liquid chromatography immediately and then daily for eight days while the admixtures were refrigerated. Sterility tests were carried out throughout the study. Data were analyzed by least-squares linear regression to test for trends. The cimetidine hydrochloride admixtures were stable while frozen for up to 30 days and for at least eight days following thawing when kept under refrigeration. Sterility of the admixture was maintained throughout the study period.

High-performance liquid chromatographic methods for determination of gentamicin in biological fluids.

A selective and sensitive methods for the determination of gentamicin in plasma and urine by high-performance liquid chromatography has been developed. Following deproteinization, the gentamicin is reacted with fluorescamine to produce a fluorescent derivative. This reaction mixture is directly chromatographed on a cation exchange column using as mobile phase acetonitrile-phosphoric acid (7:3). The gentamicin compounds elute as a single peak. Using 0.1 ml of plasma, quantitation of gentamicin concentration as low as 1 mg/l are possible. Possible interference from other aminoglycosides and antibiotics is discussed.

The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration--effect relationships.

1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half-time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(-1) after i.v. dosing and 33.5 ms . mg 1(-1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.

The bioavailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 +/- 14%, mean +/- SD) amount absorbed than did the intravenous dose. The aqueous solution (99 +/- 8%) and intravenous dose were statisticlly indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99 +/- 10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence level that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.

Evaluation of the absorption from some commercial sustained-release theophylline products.

Absorption of theophylline from three commerical products labeled as sustained release was compared to the absorption from a standard uncoated tablet (Searle 200-mg aminophylline tablet) in a single-dose study. Aminodur tablets (Cooper) and Slophyllin Gyrocap capsules (Dooner) had bioavailability (100.2% +/- 19.8% and 98.5% +/- 13.8%) statistically indistinguishable from that of the standard but showed significantly slower absorption (peak times of 10.4 +/- 2.8 and 4.36 +/- 1.35 hr) and lower peak plasma concentrations (13.9 +/- 4.5 and 22.6 +/- 3.5 micrograms/ml/g dose) than the standard (tpeak, 1.52 +/- 0.45 hr; Cpeak, 28.1 +/- 6.2 micrograms/ml/g dose). The time of the plasma concentration peak (2.47 +/- 1.38 hr) after a dose of Tedral S.A. (Warner/Chilcott) was not statistically different from that after the standard, but both the peak concentration (16.0 +/- 3.9 micrograms/ml/g dose) and availability (76.0 +/- 18.4%) were. Multiple-dose projections from single-dose data indicate that of the three test products only Aminodur maintains reasonably constant interdose plasma levels during 12 hoursly dosing. With an 8 hourly dosing schedule Gyrocaps also might be satisfactory. Reasonable predictions of the plasma concentrations arising from Aminodur doses have been made using a single-compartment body model and assuming input from an outer followed by an inner layer of the tablet.

Evaluation of the absorption from some commercial enteric-release theophylline products.

In a single-dose bioavailability study, Wales, Robinson, Columbia, and Choledyl (Warner/Chilcott) enteric-coated tablets all allowed a bioavailability of theophylline (99% +/- 25%, 102% +/- 23%, 103% +/- 18%, and 98% +/- 15%; mean +/- SD, n = 12) statistically indistinguishable from that of the standard uncoated tablet (Searle 200 mg aminophylline). Only the Wales and Choledyl tablets (7.6, 4.2 hr) could be shown (p < 0.5) to generate a peak plasma theophylline concentration later than the standard (1.4 hr). All tablet brands demonstrated a significant lag time before appearance of theophylline in the plasma, and both Wales and Choledyl tablets also had a (tpeak-tlag) statistically different from that of the standard. Despite misleading indications from the mean plasma profile (plasma concentrations at each sampling time averaged over all subjects), plasma data from the individual participants and in vitro dissolution data show that, while release of theophylline from the Wales tablet might be inordinately slow, this is not a sustained-release preparation. Of the enteric-coated tablets only the Columbia product allowed significant levels in the first sample after dosage. Five of the 18 Columbia doses gave rise to 40-99% of the peak concentration in the 1-hr sample. In vitro, it takes 39 +/- 14 min for 40% of the theophylline content of Columbia tablets to dissolve in simulated intestinal fluid. Suprisingly rapid delivery of an enteric-coated tablet to the duodenum would appear to be required to allow a significant percentage of theophylline to be dissolved and absorbed before 1 hr. None of 12 Columbia tablets tested in vitro, however, allowed dissolution of more than 1.2% of their theophylline content during 1 hr immersion in simulated gastric fluid. Since once in intestinal fluid Columbia tablets appear to dissolve more rapidly than the other enteric products, it is not clear whether the five Columbia tablets in question had imperfections or wheter, in fact, this tablet brand more closely than the others represents the ideal of immediate release once in the duodenum. Plasma samples should be taken as early as 15 min after dosage when evaluating the bioavailability of enteric release products.

Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin.

Compressed and enteric-coated acetylsalicylate (ASA) tablets have been compared in normal healthy subjects. Plasma ASA and salicylate (SA) were measured by high pressure liquid chromatography (HPLC). Platelet cyclooxygenase activity in vitro was studied by a radiometric technique. Following ingestion of 650 mg of ASA in the form of compressed tablets, cyclooxygenase activity was inhibited 95% within 45 min. Enzyme activity was observed to increase within 8 h and reached 10% of control level by 24 h. The pattern suggests that only circulating platelets are affected by ASA ingestion. Following the administration of 650 mg of ASA as enteric-coated tablets comparable inhibition of cyclooxygenase activity was observed, although the effect was delayed, reflecting the delayed appearance of ASA in the plasma. Return to control levels followed a pattern similar to that observed with the compressed tablet.