Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.

Simultaneous determination of clarithromycin and 14(R)-hydroxyclarithromycin in plasma and urine using high-performance liquid chromatography with electrochemical detection.

A sensitive method for the simultaneous high-performance liquid chromatographic determination of clarithromycin and its active metabolite in plasma and urine is described. Alkalinized samples were coextracted with an internal standard and analyzed on a C8 column using electrochemical detection. Recoveries were greater than or equal to 85% and consistent. Standard curves for plasma were linear in the range 0-2 micrograms/ml for both compounds (r greater than 0.99), with limits of quantification of approximately 10.03 micrograms/ml (0.5-ml sample). Within-day and day-to-day precision were good, with coefficients of variation mostly within +/- 5%; accuracy for both compounds were routinely within 90-110% of theoretical values. Standard curves for urine were linear in the range 0-100 micrograms/ml with limits of quantification of 0.5 micrograms/ml (0.2-ml sample). Urine assays also had similar within-day and day-to-day precisions and accuracy.

Effect of age on the pharmacokinetics of orally and intravenously administered terazosin.

Terazosin, a new long-acting selective alpha 1-receptor antagonist, was studied in a crossover trial to assess the effect of age on oral and intravenous pharmacokinetics. Thirty healthy male and female volunteers between the ages of 23 and 75 years received 1-mg oral and intravenous doses of terazosin. For both routes of administration, the only pharmacokinetic variables significantly correlated with age were terminal elimination rate constant and the area under the plasma concentration-time curve (AUC). However, the differences in half-life and AUC between the youngest and oldest subjects were modest and not of practical clinical significance. There was no evidence of an enhanced pharmacologic or toxic effect in older subjects. From these data, we conclude that the dosage of terazosin does not need to be adjusted on the basis of age alone; the dose of terazosin is titrated in all patients to the lowest effective dose that is well tolerated.

Pharmacokinetics of terazosin.

The pharmacokinetics of terazosin have been assessed in human volunteers, hypertensive patients, a limited number of elderly volunteers, and a small number of patients with congestive heart failure. Terazosin was administered intravenously and orally in doses ranging up to 7.5 mg. Following intravenous administration, the disposition of terazosin is characteristic of a two-compartment, open model that is linear and independent of dose. Orally administered terazosin is rapidly, consistently, and almost completely absorbed into the bloodstream. Peak plasma drug levels occur within one to two hours after ingestion. Approximately 90 to 94 percent of the drug is bound to plasma proteins, with the volume of distribution estimated to be 25 to 30 liters. Terazosin undergoes extensive hepatic metabolism, and the major route of elimination is via the biliary tract. Small amounts of terazosin are excreted in the urine. Plasma and renal clearances are 80 and 10 ml per minute, respectively. The mean beta-phase half-life is approximately 12 hours. The pharmacokinetics of terazosin were not influenced by age, congestive heart failure, or hypertension (other than plasma clearance). In contrast to prazosin, terazosin is completely and consistently bioavailable and has a half-life that is three to four times longer than that of prazosin. The prolonged half-life of terazosin allows once-daily dosing, which may facilitate patient compliance with drug therapy for hypertension.

Metabolism of 14C-estazolam in dogs and humans.

14C-Estazolam (2 mg) administered orally to dogs and human subjects was rapidly and completely absorbed with peak plasma levels occurring within one hour. In humans, plasma levels peaked at 103 +/- 18 ng/ml and declined monoexponentially with a half-life of 14 h. The mean concn. of estazolam in dog plasma at 0.5 h was 186 ng/ml. Six metabolites were found in dog plasma at 0.5 and 8 h, whereas only two metabolites were detected in human plasma up to 18 h. Metabolites common to both species were 1-oxo-estazolam (I) and 4-hydroxy-estazolam (IV). Major metabolites in dog and human plasma were free and conjugated 4-hydroxy-estazolam; the concn. were higher in dogs. After five days, 79% and 87% of the administered radioactivity was excreted in dog and human urine, respectively. Faecal excretion accounted for 19% of the dose in dog and 4% in man. Eleven metabolites were found in the 0-72 h urine of dogs and humans; less than 4% dose was excreted unchanged. Four metabolites were identified as: 1-oxo-estazolam (I), 4'-hydroxy-estazolam (II), 4-hydroxy-estazolam (IV) and the benzophenone (VII), as free metabolites and glucuronides. The major metabolite in dog urine was 4-hydroxy-estazolam (20% of the dose), while the predominant metabolite in human urine (17%) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. The metabolism of estazolam is similar in dog and man.

Toxicological aspects of cyclamate and cyclohexylamine.

In the late 1960s the artificial sweetener cyclamate was implicated as a bladder carcinogen in rats. This finding and other concerns about its safety ultimately led to a ban on cyclamate in the U.S. and restrictions on its use in many other countries. Since that time, the carcinogenic potential of cyclamate and cyclohexylamine, its principal metabolite, has been reevaluated in a group of well-controlled, well-designed bioassays that have failed to substantiate the earlier findings. This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine, including their effects on various organ systems, their genotoxic potential, and their effects on reproduction. In addition, the physiological disposition of cyclamate is reviewed, with particular attention directed toward the site and extent of its conversion to cyclohexylamine.

Effect of probenecid on the pharmacokinetics of cefmenoxime.

In this study, we were concerned with the effect of probenecid on the pharmacokinetics of 1,000 mg of cefmenoxime administered over a 30-min period by intravenous infusion. Each of a total of 10 subjects received cefmenoxime twice, once with and once without adjunctive probenecid. The data were fit by iterative nonlinear regression procedures to a two-compartment open pharmacokinetic model, with elimination from the central compartment. The mean calculated peak concentration, area under the curve from zero to infinity, and half-life without probenecid were 78.1 micrograms/ml, 77.2 micrograms . h/ml, and 1.14 h, respectively. When cefmenoxime was administered with probenecid, these values were 86.7 micrograms/ml, 158.2 micrograms . h/ml, and 1.78 h, respectively. Averages of about 55 and 46% of the administered doses were recovered in urine samples collected at 0 through 24 h for doses administered without and with probenecid, respectively. The mean corrected renal drug clearance was 159 and 66 ml/min without and with probenecid, respectively. Statistical significance (P less than 0.05) was demonstrated for the differences in beta half-life, (K/net), calculated peak concentration, area under the curve from 0 to infinity, and renal clearance, but not for K21, K12, volume of distribution, or alpha-phase distribution rate constant. The results of this study indicate that tubular secretion is the predominant mechanism of clearance for cefmenoxime and that probenecid alters the pharmacokinetics of the compound by competitively inhibiting its tubular secretion without affecting either the rate or the extent of its distribution.

Simultaneous analysis of the serum and urinary pharmacokinetics of fortimicin A after intravenous administration to healthy subjects.

The present study was conducted to evaluate the single-dose pharmacokinetics of the pseudodisaccharide antibiotic, fortimicin A, in humans, following intravenous infusion of 2.5, 5.0, and 7.5 mg per kg doses of the free base (as fortimicin A sulfate) to 17 volunteers who were randomly assigned to each of three dose groups containing six, six, and five subjects, respectively. Each dose was infused in 100 ml of 5% glucose/water over 57-63 min (i.e., an infusion rate of approximately 1.7 ml per min). Serum samples were obtained at 0, 1, 1.25, 1.5, 1.75, 2, 3, 5, 6, 8, and 12 h after the start of the infusion. Urine was collected in 0-4, 4-8, 8-12, and 12-24 h fractions (also relative to start of infusion). Determinations of fortimicin A concentrations were performed microbiologically on urine samples, and with a unique immunologic procedure on serum samples. Serum concentration-time and cumulative urinary excretion-time data for each subject were simultaneously fit to a two-compartment open model with zero-order absorption (i.e., infusion) and biexponential elimination. Of the six pharmacokinetic parameters studied (K21, K12, KNet, V1, cumulative fraction of drug excreted to infinite time, and renal clearance), significant (p = 0.05) dose-related differences were found only in the mean renal clearances between the 2.5 mg/kg dose group and the other two; however, this was of questionable practical importance. The overall mean beta-phase half-live was about 1.8 h, with little subject-to-subject variability.

Cefsulodin kinetics in healthy subjects after intramuscular and intravenous injection.

We evaluated cefsulodin kinetics in normal subjects after 250-, 500-, and 1,000-mg, intramuscular injections and 500-, 1,000-, and 2,000-mg 30-min intravenous infusions. Twelve plasma and four urine samples were collected in the first 12 and 24 hr. Plasma samples were analyzed by a new, highly precise high-performance liquid chromatographic procedure developed in our laboratory and urine samples were analyzed microbiologically, using Pseudomonas aeruginosa as the test organism. Mean calculated peak plasma levels from the 250-, 500-, and 1,000-mg intramuscular doses were 5.46, 11.81, and 19.40 microgram/ml. After 500-, 1,000-, and 2,000-mg intravenous infusions peak levels were 32.7, 65.7, and 190.1 microgram/ml. Data from the intramuscular doses were fitted to a one-compartment open kinetic model, yielding a mean elimination half-life (t1/2) of 1.9 hr. Data from the intravenous infusions were fitted to a two-compartment open model, with a mean beta-phase t1/2 of 1.6 hr. Mean 0- to 24-hr urinary recoveries after the three intramuscular doses were 50.0%, 54.5%, and 51.2% of total dose; after the three intravenous doses they were 60.4%, 52.4%, and 54.0%. Cefsulodin kinetics were shown to be consistent and orderly.

Intramuscular and intravenous pharmacokinetics of cefmenoxime, a new broad-spectrum cephalosporin, in healthy subjects.

This study was concerned with the single-dose, pharmacokinetics of cefmenoxime after intramuscular (i.m.) injections of 250, 500 and 1,000 mg; 1-h intravenous (i.v.) infusions of 500, 1,000, and 2,000 mg; and 5-min i.v. injections of 500, 1,000, and 2,000 mg of cefmenoxime. A total of 15 subjects were used, each receiving all three doses for one route of administration. Mean calculated peak plasma levels after the 250-, 500-, and 1,000-mg i.m. doses were 9.07, 14.68, and 26.73 micrograms/ml, respectively, occurring about 40 min after dosing. The biphasic decline in plasma levels after i.v administration was usually not apparent after i.m. dosing, because absorption of the drug from the injection depot was slower than distribution of the drug. Mean calculated peak levels from the 500-, 1,000-, and 2,000-mg i.v. doses were 22.8, 41.6, and 94.5 micrograms/ml, respectively, after the 1-h infusions and 64.1, 100.9, and 198.2 micrograms/ml, respectively after the 5-min injections. Small but statistically significant trends of decreasing alpha and increasing volume of distribution (central compartment) with increasing dose size were noted; however, this distribution phenomenon was self-compensating, resulting in no overall effect on plasma clearance. For practical purposes, the pharmacokinetics were linear. The mean 0- to 24-h urinary recoveries of cefmenoxime after the i.m. injections, i.v. infusions, and i.v. injections were 72.1, 67.5, and 74.5% respectively. Overall, the pharmacokinetics of cefmenoxime were best described by a two-compartment open model with a beta-phase half life of 0.91 h. Plasma clearance of the drug was dosage level and route independent, averaging 254 ml/min; thus, there was an excellent linear relationship between the area under the plasma level curve and the dose. The results of this study indicated that most of the drug is removed by renal mechanisms, with tubular secretion predominating.