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.

igh sialic acid content slows prourokinase turnover in rabbits.

The clearance of natural and recombinant prourokinase (proUK) from the blood of rabbits was studied by means of a double-isotope method which allowed the differential removal of two distinct proUK species to be monitored when simultaneously administered to an individual animal. In initial experiments, proUK expressed in different cell lines contained between 0 and 2.5 molecules of sialic acid per molecule of protein. A slight trend toward slower clearance of proUK with higher sialic acid content was observed but rate differences were not statistically significant. Recombinant proUK produced in CHO cells grown in flow reactors, contained unusually high levels of sialic acid in excess of 3 moles/mole protein. Controlled exposure to immobilized neuraminidase was used to remove sialic acid from this protein in defined amounts. The clearance of the parent material was biphasic with average alpha and beta half-lives of 1.7 min and 16.7 min respectively. The AUC of the parent material was only slightly lowered upon removal of 30% of the original sialic acid. Species with 60% or 90% removal of sialate were much more rapidly cleared from the circulation respectively yielding AUCs equal to 56% and 41% of that observed with the parent material. Thus proUK containing 2.5-3.5 sialic acid molecules per molecule of protein turned over significantly more slowly in rabbits than did less sialylated proUK. The clearance rate was relatively insensitive to sialic acid content between 0 and 1.5 sialic acid residues per proUK molecule.

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.

High-performance liquid chromatographic procedures for the determination of difloxacin and its metabolites in biological matrices.

A simple and extremely precise high-performance liquid chromatographic procedure has been developed for the determination of difloxacin and its metabolites in plasma and urine. Work-up of plasma samples entails ultrafiltration after addition of an internal standard in a displacing reagent containing sodium dodecyl sulfate. The ultrafiltrates are directly analyzed using a C18 reversed-phase analytical column, a soap-chromatographic mobile phase, and a fluorescence or ultraviolet detector. The mean intra-assay coefficient of variation for difloxacin over a concentration range of 10 ng/ml to 10 micrograms/ml was 0.5% when fluorescence detection and an internal standard were employed. Inter-assay coefficients of variation were approximately 2%. Recoveries of difloxacin and its metabolites were essentially quantitative and calibration curves were strictly rectilinear.

Single-dose pharmacokinetics of 3-O-demethylfortimicin A in humans after intravenous and intramuscular administration.

The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.

Single-dose pharmacokinetics of leuprolide in humans following intravenous and subcutaneous administration.

A group of six normal adult male volunteers was divided into two groups (I and II) who received bolus intravenous and subcutaneous 1-mg doses of leuprolide. The study was of a randomized, complete-crossover design. Blood was collected from 0 to 48 h postdosing, and plasma was analyzed for leuprolide using a radioimmunoassay procedure. The data from the intravenous doses were fitted to a two-compartment open model with elimination from the central compartment, assuming a bolus (instantaneous) injection. The data from the subcutaneous doses were fitted to a two-compartment open model with elimination from the central compartment and first-order (monoexponential) absorption from the injection site. Statistical moments were also calculated for both sets of data. The mean beta half-life after the intravenous dosings was 2.9 h and after the subcutaneous dosings was 3.6 h. The difference between these two values, as well as those for plasma clearance, variance in residence time, and volume of distribution at steady state was not statistically significant; however, the differences between the mean values of k21, k12, kel, apparent volume of distribution of the central compartment, mean residence time, and area under the moment curve for the routes of administration were significant (p less than 0.05). The mean residence time following the intravenous dosings averaged 3.1 h and following the subcutaneous dosings averaged 4.3 h, indicating an average mean residence time at the subcutaneous injection site of 1.2 h. The mean volume of distribution at steady state from the intravenous and subcutaneous doses were 26.5 and 37.1 L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[(Aminomethyl)aryloxy]acetic acid esters. A new class of high-ceiling diuretics. 2. Modifications of the oxyacetic side chain.

The discovery of high-ceiling natriuretic activity from a series of aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate prompted our continued investigation of this new class of (aryloxy)acetic acid diuretics. Systematic alteration of the oxyacetic side chain has shown that the carboxylic acid function is the active species in vivo and that the ethyl ester group serves as a prodrug to enhance oral absorption. Side-chain functional groups that are incapable of generating the carboxylic acid in vivo failed to impart diuretic activity to the target compounds. Additional side-chain modifications including homologation, methyl substitution, and heteroatom replacement are also described. Ring annelation of the oxyacetic side chain to a dihydrobenzofuran-2-carboxylic acid produced compound 32, which displayed the highest level of saluretic activity for this series.

Kinetics of cefsulodin in patients with renal impairment.

Kinetics of cefsulodin were determined after administration of a 500-mg dose to normal subjects and patients with various degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two-compartment model. The steady-state volume of distribution was 0.26 liters/kg regardless of renal function. When the glomerular filtration rate (GFR) was greater than 80 ml/min, the elimination half-life (t1/2) was 1.9 hr. When the GFR ranged from 79 to 53 ml/min, t1/2 was 2.9 hr. In patients with moderate renal failure, in whom the GFR was 32-22 ml/min, t1/2 was 5.7 hr. In anuric patients, t1/2 was 13.0 hr. During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 ml/min, concentration of drug in plasma was reduced by 60%, and t1/2 decreased to 2.1 hr. After dialysis the elimination rate appeared to return to that found in subjects not undergoing dialysis. While progressive renal failure slows the elimination of cefsulodin, there is a linear relationship between elimination of cefsulodin and GFR such that dosage nomograms can be developed. In patients undergoing hemodialysis, the maintenance dose of cefsulodin should be reduced to 10% of normal, and 60% of the dose should be given after hemodialysis.

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.

Precise high-performance liquid chromatographic procedure for the determination of cefsulodin, a new antipseudomonal cephalosporin antibiotic, in plasma.

A simple and precise high-performance liquid chromatographic (HPLC) procedure was developed for the determination of cefsulodin, a new antipseudomonal cephalosporin antibiotic, in plasma. The analytical procedure involved ultrafiltration of samples that were buffered to prevent cefsulodin degradation, followed by injection into an HPLC system, utilizing a C18 reversed-phase analytical column, a mobile phase of acetonitrile-modified aqueous acetate buffer, and a UV spectrophotometric detector. Because of the simplicity of the procedure, the intraassay (or approximately 2%) and interassay (or approximately 3-4%) coefficients of variation were extremely low. Recoveries of drug were essentially quantitative in freshly buffered specimens and in those stored buffered and frozen for nearly 3 months. Calibration curves were rectilinear from the limit of quantification (or approximately 0.2 microgram/ml) to 200 micrograms/ml, as demonstrated by regression correlation coefficients averaging greater than 0.999 during routine analyses.

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 renal impairment.

Cefsulodin kinetics were determined after a 500-mg dose to normal subjects and patients with varying degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two-compartment model. Steady-state volume of distribution was 0.26 l/kg regardless of renal function. When glomerular filtration rate (GFR) was more than 80 ml/min, elimination half-life (t1/2) was 1.9 hr, total body clearance (ClT) was 2.01 ml/kg/min, and renal clearance (ClR) was 1.09 ml/kg/ in. When GFR ranged from 79 to 53 ml/min, t1/2 was 2.9 hr, ClT was 1.17 ml/kg/min, and ClR was 0.65 ml/kg/min. In subjects with moderate renal failure in whom GFR was 32 to 22 ml/min, t1/2 was 5.7 hr, Clt was 0.66 ml/kg/min, and ClR was 0.26 ml/kg/min. In anuric patients t1/2 was 13.0 hr. and ClT was 0.19 ml/kg/min or 9.5% of ClT in normal subjects. There was a linear relationship between ClT and GFR such that ClT = 0.19 + 0.017 GFR (r = 0.95). During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 ml/min, plasma drug concentration was reduced by 60%, and t1/2 fell to 2.1 hr. After dialysis the elimination rate appeared to return to that in nondialysis studies. Therefore, renal failure reduces the ClT of cefsulodin. In hemodialysis patients the maintenance dose of cefsulodin should be reduced to 10% of normal and 60% of the dose should be given after hemodialysis.

A very precise high-performance liquid chromatographic procedure for the determination of cefmenoxime, a new cephalosporin antibiotic, in plasma.

A simple and very precise high-performance liquid chromatographic procedure has been developed for the determination of cefmenoxime, a new broad spectrum cephalosporin antibiotic, in plasma. The workup procedure involves ultrafiltration of samples which have been treated with sodium dodecyl sulfate to displace the drug from its binding sites on plasma proteins. The ultrafiltrates are then directly injected into a high-performance liquid chromatographic system utilizing a reversed-phase analytical column, and an ultraviolet spectrophotometric detector. The mean assay coefficient of variation over a concentration range of 0.5-200 micrograms/ml is slightly greater than 1% when either p-nitrobenzoic or p-anisic acid is used as the internal standard. Recoveries of drug are essentially quantitative at all levels investigated; hence the calibration curves are rectilinear from the limit of quantification (about 0.05 microgram/ml) to at least 200 micrograms/ml.

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.

Radioimmunoassay of carteolol in human plasma.

A radioimmunoassay for the direct measurement of carteolol, a new beta-adrenoreceptor blocker, in human plasma was developed. Carteolol was acylated to form O-glutarylcarteolol, which was conjugated to bovine serum albumin to provide the immunogen. Antibody to carteolol was raised in New Zealand albino rabbits. The tracer was the radioiodinated derivative of O-glutarylcarteolol-tyrosine methyl ester conjugate. The method is highly sensitive, with a lower quantifiable concentration of approximately 0.4 ng of carteolol/ml using 0.1 ml of plasma, and has good specificity, with the major metabolite (8-hydroxycarteolol) showing only 0.2% cross-reactivity. It is reproducible, with relative standard deviations from triplicate standard curves being mostly within +/- 8%. The method is currently being used to monitor carteolol levels in clinical samples.