Bioavailability of amiodarone tablets administered with and without food in healthy subjects.

The tablet form of amiodarone is indicated for the treatment of recurrent ventricular fibrillation or hemodynamically unstable ventricular tachycardia. It is recommended that the tablet be taken with meals in cases of gastrointestinal intolerance. However, the effect of food on its bioavailability is unknown. The primary objective of this study was to determine the effect of food on the bioavailability of amiodarone. This was a 2-period crossover study conducted in 30 healthy male subjects. Subjects were randomly assigned to 1 of 2 sequences in which the following 2 treatments were administered: (1) a single-dose of amiodarone (three 200-mg Cordarone tablets) after an overnight fast, and (2) the same dose immediately after a standard high-fat breakfast. Plasma concentrations of amiodarone and desethylamiodarone (DEA) were measured for 6 weeks after each dose. Food enhanced the extent of absorption, resulting in a peak concentration (Cmax) and area under the curve (AUCT) 3.8 and 2.4 times the respective values under fasting conditions. Food also significantly increased the rate of absorption, reducing the time (tmax) to Cmax from 7.1 to 4.5 hours. The effect of food on DEA levels was significant but less pronounced. An in vitro dissolution study confirmed a marked difference between amiodarone release under simulated fed and fasting conditions. Thus, food significantly enhances both the rate and extent of absorption of amiodarone, which is attributed partially to the effect of food on drug release from its formulation. Therefore, it is recommended that amiodarone tablets be taken consistently with meals.

Chiral bioequivalence: effect of absorption rate on racemic etodolac.

BACKGROUND: For many racemic drugs, bioequivalence assessment based on isomer-nonspecific assays is appropriate because enantiomeric area under the concentration-time curve (AUC) exposure ratios are close to unity. Use of nonspecific methods in cases in which the ratio is substantially greater or less than 1, however, may obscure real therapeutic differences among formulations, especially if the enantiomers exhibit differing pharmacological potencies. OBJECTIVE: To examine the influence of absorption rate on etodolac bioequivalence as measured by total [(R,S)-] and (S)-etodolac. DESIGN: Single dose, 3-period, crossover, pharmacokinetic study in 24 healthy volunteers in which the administration rate of etodolac was varied. METHODS: Participants received etodolac 400mg in solution, given as a single dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPLC assay. The enantiomer ratio was similarly measured by HPLC. RESULTS: Bioequivalence parameters derived for both unresolved and (S)etodolac indicate that peak plasma drug concentration (Cmax) was not bioequivalent. By delaying absorption, bioequivalence was lost. CONCLUSIONS: Collectively, these data demonstrate that bioequivalence between 2 products of etodolac based on enantiomerically nonspecific criteria alone may not generalise to the pharmacologically relevant (S)-enantiomer. This suggests that enantiospecific assays are necessary for bioequivalence assessments.

The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine.

The influence of cimetidine on the disposition pharmacokinetics of the antidepressant drug, venlafaxine, and its active metabolite, O-desmethylvenlafaxine, was examined in 18 healthy young men and women. The steady-state pharmacokinetic profiles of venlafaxine and O-desmethylvenlafaxine were evaluated during a 24-hour period after 5 days of treatment with venlafaxine (50 mg three times a day) and during a second 24-hour period after 5 days of combination treatment with venlafaxine (50 mg three times a day) and cimetidine (800 mg once a day). The apparent oral clearance of venlafaxine decreased significantly in the presence of cimetidine and the average steady-state plasma concentration of venlafaxine increased significantly in the presence of cimetidine, but there were no changes in the corresponding concentrations of the active metabolite. However, O-desmethylvenlafaxine exhibits pharmacologic activity that is approximately equimolar to that of venlafaxine, and the sum of venlafaxine plus O-desmethylvenlafaxine plasma concentrations was increased by an average of only 13%. Therefore, the effect of cimetidine coadministration is not expected to result in clinically important alterations in the response to venlafaxine in patients with depression. This may not be true, however, for patients with compromised hepatic metabolic function.

Dissolution difference between acidic and neutral media of acetaminophen tablets containing a super disintegrant and a soluble excipient. II.

The disintegration and dissolution of acetaminophen tablets containing sucrose and Ac-Di-Sol/Primojel was significantly different between acidic and neutral media. The purpose of this study was to investigate the mechanism of this phenomenon and to propose a way of reducing the dissolution difference between the two media. Tablets of different combinations of active ingredient, sucrose, and Ac-Di-Sol/Primojel were prepared and their dissolution in various media was evaluated. The dissolution differences were found to be largely related to the hydrophobicity of the active ingredient and pH difference of the two media. This difference was even more evident under the condition where acetaminophen, sucrose, and Primojel were combined. The dissolution difference was therefore attributed to the depressed function of Primojel in the acidic medium, the stronger binding of sucrose, the hydrophobicity of the active ingredient and pH difference of the two media. Increasing the concentration of Primojel or incorporating the surfactant in the tablet can thus greatly decrease the dissolution difference between acidic and neutral media.

Population pharmacokinetics of intravenous amiodarone and comparison with two-stage pharmacokinetic analysis.

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration-time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight-corrected) also were calculated using two-stage analysis and were compared with the results obtained from the mixed-effects analysis. The population plasma concentration-time profile of amiodarone was best described by a four-compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two-stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (> or = 65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half-life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two-stage analysis.

Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine.

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two-period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model-dependent calculation of the first-order absorption rate constant, and a model-independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O-demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50-mg tablet. A standard, medium-fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation.

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and ethanol.

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self-medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double-blind, placebo-controlled, two-period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O-desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.

Pharmacokinetic-pharmacodynamic relationships of bromfenac in mice and humans.

The relationship between pharmacodynamic effect and plasma concentrations of the analgesic bromfenac was assessed retrospectively. The drug was administered in single doses of 5, 10, 25, 50, or 100 mg to patients with oral surgery pain. Concentration-effect curves were generated by a semiparametric pharmacokinetic-pharmacodynamic procedure. The bromfenac EC50 (the effect site concentration giving 50% of the maximum effect) was estimated to be 0.36 microgram/ml in patients when all five dose groups were combined, and an Emax model was used for pharmacodynamic response. A similar EC50 value, 0.40 microgram/ml, was obtained when bromfenac was tested in a mouse pain model. On the basis of combined-dose data, effect site concentrations were predicted to be above the analgesic EC50 for approximately 7-8 hours after a 50-mg bromfenac dose was taken in the fasting state. Predictions based on a pharmacokinetic-pharmacodynamic modeling procedure were in reasonable agreement with the clinical observations.

Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics.

This single- and multiple-dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O-desmethylvenlafaxine. The subjects were 18 elderly (age 60-80 yrs) and 18 young (age 21-44 yrs) subjects, 9 men and 9 women per age group. They received a single 50-mg venlafaxine dose followed by 50-mg doses every 8 hours for 5 days. No significant differences in venlafaxine single-dose pharmacokinetics were seen between age groups, but the steady-state half-life increased 24% in the elderly. For O-desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half-life (13.2 vs 10.3 hrs), and 14% greater steady-state half-life. For the composite (venlafaxine+O-desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady-state area under the curve (AUC* = AUC+activity factor AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.

Population pharmacokinetics of intravenous amiodarone in patients with refractory ventricular tachycardia/fibrillation.

A population approach was used to determine the pharmacokinetics of amiodarone in 245 patients receiving intravenous amiodarone for the short-term treatment of refractory, hemodynamically destabilizing, ventricular tachycardia and/or fibrillation. A two-compartment model employing proportional statistical models to estimate intersubject variability and an additive-proportional model to estimate residual error were found to best describe the data. The mean (% coefficient of variation, CV) value for clearance was 0.22 L/hr/kg (13%), central volume of distribution was 0.30 L/kg (11%), peripheral volume of distribution was 10.0 L/kg (9.5%), and intercompartmental clearance was 0.71 L/hr/kg (16%). The mean (%CV) intersubject variance estimates were 1.52 (31%) for clearance, 0.37 (46%) for central volume, 0.37 (67%) for peripheral volume, and 0.44 (39%) for intercompartmental clearance. The estimate of residual error (%CV) was 0.53 (13%). Age, gender, height, serum creatinine concentration, serum alkaline phosphatase activity, ejection fraction, and therapeutic response to treatment did not contribute to the variability in patient pharmacokinetics. It was concluded that the pharmacokinetic parameters of amiodarone in these patients were similar to those reported for healthy volunteers and were similarly variable. Estimates of pharmacokinetic parameters made during short periods of observation may not be entirely consistent with parameters estimated during prolonged periods of observation of healthy volunteers who receive single doses.

Pharmacokinetic interaction between multiple-dose venlafaxine and single-dose lithium.

Venlafaxine is a structurally novel antidepressant. Because lithium and antidepressants may be administered concomitantly, it is important to determine whether the disposition of venlafaxine and lithium is affected by coadministration. An open-label study was conducted to evaluate the effects of multiple-dose, steady-state venlafaxine administration on the pharmacokinetics of a single oral dose of lithium. Analogously, the effects of administration of a single-dose of lithium on the disposition of venlafaxine and its active metabolite, O-desmethylvenlafaxine, after multiple-dose administration of venlafaxine were assessed. Administration of 600 mg lithium carbonate did not affect venlafaxine absorption. Lithium significantly reduced the renal clearance of venlafaxine from 0.053 to 0.027 L/h/kg. However, renal excretion is not a major elimination pathway for venlafaxine; thus, lithium did not affect the total clearance of venlafaxine. Lithium administration had similar effects on elimination of O-desmethylvenlafaxine. Multiple-dose administration of 50 mg of venlafaxine every 8 hours produced a slight increase in the rate of lithium absorption, but did not affect the extent of lithium absorption. Total clearance (0.026 L/h/kg) and steady-state volume of distribution (0.71 L/kg) of lithium were not affected by administration of venlafaxine. Thus, there were no clinically significant pharmacokinetic interactions between venlafaxine and lithium.

Tolrestat pharmacokinetic and pharmacodynamic effects on red blood cell sorbitol levels in normal volunteers and in patients with insulin-dependent diabetes.

OBJECTIVES: To examine the effect of diabetes mellitus on the pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drugs. METHODS: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. RESULTS: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t1/2) was 13 +/- 3 hours (mean +/- SD) and the apparent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the values in patients with type I diabetes mellitus (t1/2 = 14 +/- 4 hours; CL/F = 55 +/- 10 ml/hr/kg). Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhibition constant (IC50) for production of sorbitol by aldose reductase. The removal of sorbitol (kout) was slower in patients with diabetes. The plasma IC50 averaged 2.0 +/- 1.3 micrograms/ml in normal subjects and 2.5 +/- 1.9 micrograms/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (fu = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbitol accumulation in human red blood cells. CONCLUSIONS: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.

The pharmacokinetics of venlafaxine when given in a twice-daily regimen.

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O-desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open-label, randomized, two-period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O-desmethylvenlafaxine were obtained during a 24-hour steady-state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0-24), trough concentration, or fluctuation ratio for venlafaxine or O-desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0-24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150-mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O-desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

The effect of renal disease on the disposition of venlafaxine.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

Effect of hypothyroidism on the in vitro release of atrial natriuretic peptide in response to sodium challenge in rats.

The release of atrial natriuretic peptide (ANP) in vitro in response to the challenge of sodium chloride was investigated in hypothyroid rats. Male rats were injected with propylthiouracil (PTU, 20mg/kg BW, intraperitoneally), or PTU and thyroxine (T4, 20 micrograms/kg BW, subcutaneously) once daily for 14 days before decapitation. Rats injected with saline were used as control. The plasma samples were collected and extracted by Sep-Pak C18 cartridge. The concentrations of ANP in extracted plasma were measured by a radioimmunoassay (RIA). PTU-induced hypothyroidism resulted in decreased concentrations of plasma ANP. Replacement of T4 in PTU-treated hypothyroid rats restored the plasma concentrations of ANP to normal levels. Furthermore, we examined the right atrial ANP contents and the in vitro release of ANP in PTU-treated rats and control animals. The right atrium was excised and divided into 5 equal pieces, one was homogenized with 0.1 N HCl and extracted by Sep-Pak C18 immediately, and the others were incubated with Locke's solution at 37 degrees C. After basal incubation for 30 min, rat atrial tissues were then incubated with 154, 160, or 165 mM NaCl for 30 min. The concentrations of ANP in extracted atrial tissue and medium samples were also measured by RIA. Decreased atrial contents of ANP were noted in hypothyroid rats. The in vitro release of ANP in response to 165 mM sodium ion was significantly lower in PTU than in saline-injected animals. These results suggest that lower concentration of plasma ANP in hypothyroid rats is at least in part due to impairment of stimulation-secretion responses of right atria during thyroid hypofunction in rats.

Increased concentrations of atrial and plasma atrial natriuretic peptide in castrated male rats.

The effects of orchiectomy and testosterone replacement on the plasma concentration and the atrial stores of atrial natriuretic peptide (ANP) were studied in the rats. Male rats were orchiectomized (Orc) three weeks before replacement with testosterone propionate (TP, 20 mg/ml/kg body weight) or sesame oil for five days. Immunoreactive ANP (IR-ANP) in the extracted right atria and plasma of experimental rats was measured. Plasma ANP concentrations were 206 +/- 22, 927 +/- 151, and 264 +/- 61 pg/ml in normal control, Orc, and Orc + TP rats, respectively. ANP contents in right atria were higher in Orc (108 +/- 9 ng/mg tissue) and TP-treated Orc rats (123 +/- 9 ng/mg tissue) than in normal animals (32 +/- 7 ng/mg tissue). These results indicate an increased plasma concentration and atrial stores in the castrated male rats. Replacement of testosterone in the castrated male rats does not decrease the atrial ANP stores, but decreases the plasma ANP concentration.

Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite.

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

The effect of renal disease on tolrestat pharmacokinetics.

Many patients with diabetes who may benefit from treatment with tolrestat, a new aldose reductase inhibitor, will have nephropathy. Therefore the effect of renal dysfunction on the pharmacokinetics of tolrestat was evaluated in eight subjects maintained on hemodialysis, 11 subjects with partial renal impairment (creatinine clearance values ranging from 14 to 80 ml/min/1.73 m2), and eight normal subjects. Each subject received a single oral dose of 200 mg tolrestat. Blood and urine samples were collected during a 48-hour period, and tolrestat concentrations were measured by HPLC. Renal dysfunction had no apparent effect on the rate of absorption or volume of distribution of tolrestat. However, tolrestat clearance was significantly reduced from 30 +/- 3 (SD) ml/hr/kg in the normal subjects to 15 +/- 5 ml/hr/kg in the subjects receiving dialysis, and tolrestat half-life was prolonged from 11 to 16 hours. Therefore a reduction in tolrestat dose is suggested for patients with severe renal impairment.

The absolute bioavailability and dose proportionality of intravenous and oral dosage regimens of recainam.

Recainam is a novel class I antiarrhythmic agent with electrophysiologic characteristics of all three subclasses. The authors evaluated the absolute bioavailability and dose proportionality of three oral doses and two 2-stage intravenous (IV) infusion doses. Single oral doses of 200, 400, and 800 mg and IV infusions consisting of 0.8 mg/kg/5 min + 1.2 mg/kg/hr (3.75 mg/kg) and 1.6 mg/kg/5 min + 1.2 mg/kg/hr for 4 hours and 55 minutes (7.50 mg/kg) were administered to 15 healthy men. Plasma and urine samples were collected during the 36-hour period after drug administration and analyzed for recainam concentrations by HPLC. No significant differences were found in any of the pharmacokinetic parameters between the two IV dosage regimens. The absolute bioavailability of orally administered recainam increased from 73% for the 200 mg dose to 81% and 84% for the 400 and 800 mg doses, respectively. Dose proportionality deviated from linearity by 13% for the 200 vs. 400 mg doses, and 10% for the 400 vs. 800 mg doses. The slight deviation from linearity was apparently caused by increased absorption at the higher oral doses. The slight disproportionality in the disposition of recainam is not expected to be clinically significant.