Influence of concomitant quinidine administration on dextromethorphan disposition in rats.

High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague-Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI-LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED(50) of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.

Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial.

BACKGROUND: Recurrent herpes simplex labialis (HSL) occurs in 20% to 40% of the US population. Although the disease is self-limiting in persons with a healthy immune response, patients seek treatment because of the discomfort and visibility of a recurrent lesion. OBJECTIVE: Our purpose was to determine whether docosanol 10% cream (docosanol) is efficacious compared with placebo for the topical treatment of episodes of acute HSL. METHODS: Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of HSL, were randomized to receive either docosanol or polyethylene glycol placebo and initiated therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times daily until healing occurred (ie, the crust fell off spontaneously or there was no longer evidence of an active lesion) with twice-daily visits. RESULTS: The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than observed in the 367 placebo-treated patients (P =.008; 95% confidence interval [CI]: 2, 22). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P =.002; 95% CI: 3, 16.5); (2) complete healing of classic lesions (P =.023; 95% CI: 1, 24.5); and (3) cessation of the ulcer or soft crust stage of classic lesions (P <.001; 95% CI: 8, 25). Aborted episodes were experienced by 40% of the docosanol recipients versus 34% of placebo recipients (P =.109; 95% CI for odds ratio: 0.95, 1.73). Adverse experiences with docosanol were mild and similar to those with placebo. CONCLUSION: Docosanol applied 5 times daily is safe and effective in the treatment of recurrent HSL. Differences in healing time compared favorably with those reported for the only treatment of HSL that has been approved by the Food and Drug Administration.

Pharmacokinetics of oral pramiracetam in normal volunteers.

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (+/- SD) peak plasma concentrations of the four dose groups (2.71 +/- 0.54, 5.40 +/- 1.34, 6.13 +/- 0.71, 8.98 +/- 0.71 micrograms/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5 hours), the mean total body clearance (4.45-4.85 mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.

The effect of food and antacid on the absorption of fendosal.

Fendosal (200 mg) was given orally to each of two separate groups of twelve healthy male volunteers on separate occasions to assess the influence of food or antacid on the bioavailability of fendosal. Blood samples (20 ml) were drawn during 12 hours post-dosing and fendosal plasma concentrations were quantitated by a validated fluorescence technique. Food was shown to have no significant effect (p greater than 0.05) on fendosal bioavailability. However, the bioavailability of fendosal in the presence of an antacid was reduced by 80 per cent. In vitro studies suggested that a complexation between unionized fendosal and the metal ions contained in the antacid may be responsible for the decrease in the rate and extent of absorption observed in vivo.

Bioinequivalence of erythromycin ethylsuccinate and enteric-coated erythromycin pellets following multiple oral doses.

Bioequivalence comparisons between erythromycin ethylsuccinate and an enteric-coated erythromycin base pellet product were made following multiple-dose, oral administration. Twenty-four volunteers participated in a ten-dose protocol (one dosage unit every six hours) using a complete crossover design. Plasma samples were assayed using a microbiological method specific for erythromycin base in the presence of the ester. Without correcting for the differences in doses administered, the amount of active erythromycin base absorbed from the enteric-coated pellet (250 mg base) was five to seven times that absorbed from the erythromycin ethylsuccinate product (400 mg base equivalent) at steady state. Erythromycin ethylsuccinate is not bioequivalent to an enteric-coated erythromycin base pellet product. The lower bioavailability of the ethylsuccinate may be due to instability in the acidic medium of the stomach.

Dose-dependent pharmacokinetics and hepatobiliary transport of bromophenol blue in the beagle.

The pharmacokinetic profile of bromophenol blue (I) in the plasma, urine, and bile of beagle dogs was determined after intravenous administration of 5-, 20-, and 30-mg/kg doses. In addition, two competitors, probenecid and phenylbutazone, were interacted with I in vivo and with I and rat liver cytoplasmic protein fractions Y and Z in vitro as a means of elucidating the mechanism of intrahepatic transport of I. Compound I was determined spectrophotometrically at 587 nm. In plasma, I displayed apparent first-order dose-dependent kinetics. The percentage of I bound to plasma proteins was approximately 92.5% over the dose range studied. Consecutive injections of equal doses of I produced statistically different terminal half-lives (p less than 0.05), suggesting the possibility of a saturable uptake process. In the presence of each competitor, the disposition of I was altered significantly (p less than 0.05): phenylbutazone displaced I from plasma protein, while probenecid decreased the binding of I to liver proteins in the Z-fraction. The Z-fraction bound a larger amount of I than the Y-fraction, suggesting a larger binding capacity. Under no circumstances was the binding of I to the Y-fraction altered. Cumulative biliary excretion data showed that the elimination of I in bile accounted for 92-99% of the dose delivered. The biliary excretion sigma- plots displayed no dose dependency, suggesting that the dose-dependent plasma half-life is due to a dose-dependent liver uptake (as opposed to elimination) process.

Effect of nonuniform bile flow rate on the rate of biliary excretion of bromophenol blue in the beagle.

Following the intravenous administration of bromophenol blue to beagle dogs, graphs of the biliary excretion rate versus time displayed drastic fluctuations which render them of little value for standard pharmacokinetic modeling purposes. It was shown that these fluctuations in excretion rate are highly correlated with corresponding fluctuations in the bile flow rate. An expression was derived which accounts for the primary effect of nonuniform bile flow rate on the biliary excretion rate. This treatment would enable the use of such biliary excretion rate data for pharmacokinetic modeling. Secondary effects of nonuniform bile flow on the biliary excretion rate are also discussed. It is suggested that the modeling of other flow rate-dependent elimination processes could benefit from such a treatment.

The pharmacokinetics of intramuscular gold sodium thiomalate in normal volunteers.

Four normal male volunteers participated in a study designed to examine the disposition of gold given intramuscularly as gold sodium thiomalate. Blood samples were collected for 32 days following the administration of 10 mg of gold sodium thiomalate. Plasma gold concentrations were determined by atomic absorption spectrometry. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 25 days. Apparent total body clearance of gold was 7.0 +/- 0.6 ml kg-1 day-1 and the apparent volume of distribution was 0.26 +/- 0.051 kg-1. These pharmacokinetic data are in contrast to previous data from other investigators who have reported half-lives of approximately 5 days. Data from the current study provide a sound rationale for the currently used empiric dosing regimens.

Dose-dependent pharmacokinetics and biliary excretion of bromophenol blue in the rat.

Concentrations of bromophenol blue (I) in plasma, urine, and bile were determined spectrophotometrically after intravenous bolus injections and infusions in rats. The plasma concentrations were found to decrease monoexponentially after all doses except the highest, where the decrease was biexponential. Although the disposition kinetics of I were apparently first-order at all doses, the half-life increased with increasing dose. The area under the plasma concentration-time curve (AUC0-infinity) increased disproportionately with increasing dose. The binding of I to rat plasma proteins, as determined by equilibrium dialysis, showed that the fraction bound (96%) remained constant in the concentration range of 10-300 micrograms/ml. Plasma concentrations were determined at time zero after intravenous administration and after a second dose administered 20 min later when plasma concentrations from the first dose were minimal. The apparent first-order elimination rate constant for the plasma concentration decline following the second dose was significantly less than after the first dose, indicating that the residual dye in the liver altered the elimination of I after the second dose. The fraction of the dose in the liver decreased with increasing dose, indicating a saturable uptake process. The biliary excretion profile reflected the uptake saturation that occurred in the liver and demonstrated that the biliary excretion of I depended on the amount present in the liver. When liver damage was induced by exposure to carbon tetrachloride, dye concentrations in the plasma, liver, and kidney increased markedly.

Pharmacokinetics and efficacy of pirmenol hydrochloride in the treatment of ventricular dysrhythmia.

Pirmenol hydrochloride (CI-845), a new antiarrhythmic agent available for both oral and intravenous administration, was given to seven patients with chronic ventricular dysrhythmia in an open-label fashion. After intravenous infusion of 150 mg over 30 min, the mean (+/- SD) peak plasma concentration achieved was 2.14 +/- 0.75 microgram/ml. The terminal elimination half-life, the volume of the central compartment, and the total body clearance averaged 6.5 h, 0.70 +/- 0.36 L/kg, and 3.0 +/- 2.6 ml/min/kg, respectively. After a single 150-mg oral dose, the peak plasma concentration of 1.3 +/- 0.55 microgram/ml was achieved 1 to 3 h after dosing. The mean apparent elimination half-life was 7.6 h. An estimated absorption lag time ranging from 14 to 37 min was observed in all but one patient. The mean absolute bioavailability for the oral dose was 87%. Dysrhythmia data were available in six patients. Complete (100%) suppression of ventricular ectopic beats occurred in four patients for 1/2 to 15 h after intravenous infusion, and in three patients for 7 to 25 h after oral dose. This suppression occurred with a plasma pirmenol level as low as 0.4 microgram/ml. No significant side effects were observed.

The effect of probenecid on nafcillin disposition.

Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup-plate technique with M. luteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration-time curve (AUC) two-fold and decreased the total body clearance significantly with decreases in both renal and non-renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non-renal clearances of nafcillin.

Disposition and absolute bioavailability of furosemide in healthy males.

Furosemide (40 mg) was administered to 18 healthy adult males as an intravenous dose, an oral solution, and in tablet form. The pharmacokinetics of intravenous furosemide were studied, determining a total body clearance rate of 117.6 +/- 41.3 ml/min and a harmonic mean half-life of 78 min. The mean absolute bioavailability determined by ratio of areas under the plasma-time curves was 64 and 71% for the solution and tablet, respectively. The mean absolute bioavailability determined by the ratio of urinary cumulative excretion data was 61 and 66% for the solution and tablet, respectively. The absolute bioavailability of furosemide determined with plasma and urine data were not significantly different. Thus, urine data alone may be used to establish bioavailability of furosemide. Inspection of plasma-time curves revealed secondary maxima in several subjects, suggesting enterohepatic cycling.

Pharmacokinetics of gold sodium thiomalate.

Two normal males participated in a study designed to examine the disposition of gold given intravenously and intramuscularly as gold sodium thiomalate. Blood samples were collected for 30 days, urine and feces for ten. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 12.5 days. Absolute bioavailability of IM gold sodium thiomalate appears to be variable with one subject having complete absorption and the other absorbing 64% of the administered IM dose. The major route of elimination of an IV dose of gold sodium thiomalate is urinary excretion, with a mean of 35% of the dose found in the urine in ten days. Fecal elimination accounts for an additional 9.4% of the IV dose excreted in ten days, probably as a result of biliary secretion.

Clodronate kinetics and bioavailability.

Carbon 13-labeled clodronate disodium was given to healthy adult men by intravenous infusion and orally in a crossover design. Serum and urine levels were determined as a function of time by isotope-ratio mass spectrometry. Clodronate disodium (Cl2/MDP) is primarily excreted unchanged by the kidney; more than 80% of the intravenous dose was recovered within 48 hr. The serum concentrations-time curve over the first 8 hr after intravenous dosing appears biexponential with the disposition phase having a harmonic mean half-life (t 1/2) of 2 hr. The mean serum clearance was found to be 1.4 ml min-1 kg-1 and the apparent volume of distribution was approximately 25% of body weight. Simulations and computer fitting of the cumulative urinary excretion and urinary excretion rates based on the biexponential serum decay curve demonstrated the presence of a slow disposition component with a t 1/2 of 12.8 hr. Thus, the disposition kinetics of Cl2MDP appear to be triexponentials, although the slowest component is not of major significance after a single dose and could not be verified because of a lack of serum data after 8 hr. Cl2MDP is poorly absorbed with an absolute bioavailability of only 1% to 2%.

High-performance liquid chromatographic analysis of triamterene and p-hydroxytriamterene in plasma.

A rapid and sensitive high-performance liquid chromatographic assay was developed for triamterene and 6-p-hydroxytriamterene in plasma. Plasma (0.5 ml), after addition of the internal standard, was extracted with 10 ml of ether-isopropanol (95:5). After thorough mixing and separation of phases, the organic layer was evaporated to dryness under nitrogen. The residue was reconstituted with 500 microliters of mobile phase [acetonitrile-water-acetic acid (60:39.5:0.5)], and 100 microliters was injected into the chromatograph. Chromatographic separation was carried out on a C18 muBondapak column at a flow rate of 1 ml/min. Detection of compounds in the column eluent was by UV absorption at 365 nm. The retention times for 6-p-hydroxytriamterene, triamterene, and the internal standard were 7.5, 9.0, and 12.0 min, respectively. The lower limit of detection for each compound was 20 ng/ml. Recoveries of triamterene and 6-p-hydroxytriamterene were 91--99 and 828--95%, respectively, over a 40--240-ng/ml range.

Digoxin pharmacokinetics, bioavailability, efficacy, and dosage regimens in the horse.

The pharmacokinetics of IV administered digoxin and the bioavailability of intragastrically administered powdered digoxin tables suspended in water were investigated in 6 clinically normal adult horses by 125I radioimmunoassay. The effect of 3 to 5 sequential IV doses of 5 micrograms of digoxin/kg of body weight at 2-hour intervals on a left ventricular index of contractility (Vmax) was assessed in 5 clinically normal horses. Standard pharmacokinetic equations and mean pharmacokinetic variables were used to derive parenteral and oral (loading and maintenance) doses for digoxin in horses. The calculated dosage regimens were administered and resulting plasma digoxin concentrations were monitored in 5 horses and 1 pony. Digoxin disposition after IV injection was triexponential. A rapid distributive phase with a half life (t 1/2 of 15 minutes was followed by a slow distributive phase with a t 1/2 of 4.1 hours. The biological disposition t 1/2 was 23.1 hours. The volume of distribution by extrapolation was 6.79 L/kg of body weight and 4.89 L/kg by the area method. The average bioavailability estimate for intragastrically administered digoxin was 19.2%. The Vmax increased significantly (P < 0.01) after IV digoxin administration. Greatest changes in Vmax were recorded after the first 2 injections (5 micrograms of digoxin/kg) corresponding to plasma digoxin concentrations of 0.83 and 1.68 ng/ml. Doses of digoxin were calculated as follows: IV loading 14, IV maintenance 7, oral loading 70, and oral maintenance 35 micrograms/kg/24 hours. When these doses were given to a group of horses, plasma digoxin concentrations measured 12 and 24 hours after administrated were mostly in the proposed therapeutic, nontoxic range of 0.5 to 2.0 ng/ml.

Pharmacokinetics, bioavailability, and dosage regimens of digoxin in dogs.

Digoxin, 30 micrograms/kg, was given by IV injection and orally, in the forms of pediatric elixir and tablet, on three separate occasions to six healthy dogs. Multiple serum samples were collected at timed intervals and assayed by radioimmunoassay. Data were analyzed, using nonlinear least squares regression analysis. The mean serum digoxin-time relationship was triexponential. Rapid and slow distributive phases with half lives of 9 minutes and 4.7 hours were followed by a biological disposition phase with a half life of 30.1 hours. Mean volume of distribution by extrapolation was 15.6 L/kg. When calculated by the area method, mean volume of distribution was 12.4 L/kg. Digoxin elixir was rapidly absorbed, with a mean bioavailability estimate of 71.4 +/- 8.2% SD. Digoxin tablets were less rapidly and less completely absorbed, with a mean bioavailability estimate of 58.0 +/- 11.6%. Data collected in this series of experiments and data from the literature were applied to standard pharmacokinetic equations to formulate loading and maintenance doses of digoxin for the IV injection, the elixir, and the tablet. Mean loading doses were, in micrograms/kg/24 hours: 27, 38, and 45 for the IV injection, elixir, and tablet, respectively. Corresponding mean maintenance doses were 13, 18, and 23.