Biomedical subjects

G R Granneman

Publications and source records attributed to G R Granneman.

81 records · Page 5Linked to original sources

PubMed1982

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.

Cefsulodin↗

PubMed1982

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.

Adult↗

PubMed1982

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.

Adult↗

PubMed1982

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.

Adult↗

PubMedDate not supplied

The hepatotoxicity of valproic acid and its metabolites in rats. I. Toxicologic, biochemical and histopathologic studies.

Valproic acid (VPA), its unsaturated metabolites and pent-4-enoate (4-PA) were studied for potential hepatotoxicity in rats. 4-PA, 4-en-VPA and 2,4-dien-VPA were potent inducers of microvesicular steatosis in young rats. Microvesicular steatosis induced by the 4-en-VPA was accompanied by ultrastructural changes characterized by myeloid bodies, lipid vacuoles and mitochondrial abnormalities. Myeloid bodies and lipid vacuoles were seen to a lesser extent in 2,4-dien-VPA and 4-PA-treated rats. VPA failed to induce discernible liver lesions in young rats even at near lethal doses of 700 mg per kg per day. The drug did, however, induce hepatic lipid accumulation in mature rats and in young rats dosed concomitantly with phenobarbital. beta-oxidation inhibition and several other biochemical alterations were observed in rats dosed with VPA, its unsaturated metabolites and 4-PA. It was suggested that beta-oxidation inhibition observed in both VPA and en-metabolite-treated rats occurred by different mechanisms. VPA inhibits by a transient sequestering of CoA while the CoA esters of some en-VPA-metabolites, particularly 4-en-VPA, inhibit specific enzyme(s) in the beta-oxidation sequences.

Age Factors↗

PubMedDate not supplied

The hepatotoxicity of valproic acid and its metabolites in rats. II. Intermediary and valproic acid metabolism.

The role of metabolites in valproic acid (VPA)-associated hepatotoxicity was studied in rats. The most steatogenic mono-unsaturated metabolite, 4-en-VPA, caused the greatest changes in indicators of beta-oxidation inhibition (dicarboxylic aciduria, beta-hydroxybutyrate reduction); however, the biochemical effects were much less pronounced than those reported for hypoglycin. Steatosis in VPA-treated rats occurred only at nearly lethal doses. Phenobarbital induction was confirmed as a predisposing factor; however, it appeared not to greatly enhance production of 4-en-VPA or its recognized metabolites, which collectively comprised only 0.5% of the dose. Elevated oxo-VPA metabolites in serum and 2-propylglutarate in liver were associated with toxicity. Among the newly discovered minor metabolites with possible biologic effects were diols (suggesting epoxide precursors) and a series of dienes and trienes. The rarity of severe human hepatotoxicity indicates that, normally, beta-oxidation inhibition is compensated, and cellular defense mechanisms prevail over reactive metabolites. This requires adequate nutrition; on the other hand, severe glycogen depletion may promote toxicity by compromising glucuronidation, the major clearance route. Other literature comments are also supported: (i) caution is indicated for patients with various unusual congenital disorders (e.g., organic acidurias or other mitochondrial defects), and (ii) monotherapy obviates both the predisposition to toxicity and the requirement of large doses to produce therapeutic levels.

Animals↗

PubMedDate not supplied

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.

Adult↗

PubMedDate not supplied

Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a new renin inhibitor). I: Single dose study.

This study describes the relationship between the measured effects (angiotensin I and renal plasma flow) and plasma drug levels using a combined pharmacokinetic-pharmacodynamic model after 90 min iv infusion of enalkiren in 15 healthy, salt-depleted subjects. Doses from 0.002 to 0.512 mg/kg were evaluated. One hour prior to enalkiren dosing, para-aminohippuric acid infusion was started for each subject and continued until 3 hr after the start of enalkiren infusion. Timed blood samples were obtained to measure enalkiren, para-aminohippuric acid, and angiotensin I levels in plasma. Enalkiren-induced effect changes lagged in time behind the plasma enalkiren level changes, showing a counterclockwise hysteresis loop. To relate the temporal relationship of effect changes accurately to plasma drug levels, a pharmacokinetic model was combined with a pharmacokinetic model that incorporated a hypothetical effect compartment. The magnitude of the time lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma enalkiren levels (t1/2keo). The t1/2keo for angiotensin I (0.002 hr) is significantly shorter than that of renal plasma flow (0.267 hr), indicating that enalkiren equilibrates more rapidly with the angiotensin I-related effect compartment than the renal plasma flow-related effect compartment. Moreover, the model allows for estimation of the effect site concentration that causes one-half of the maximal predicted effect (EC50), which is a measure of an individual's sensitivity to enalkiren. The EC50 of angiotensin I (81.1 ng/ml) is substantially lower than that of renal plasma flow (4414 ng/ml), indicating that angiotensin I may be a more sensitive measure of enalkiren effects than renal plasma flow.

Adult↗

PubMedDate not supplied

Differences in the stereoselective pharmacokinetics of pazinaclone (DN-2327), a new anxiolytic, and its active metabolite after intravenous and oral single doses to dogs.

The stereoselective pharmacokinetics of the new nonbenzodiazepine anxiolytic compound pazinaclone (DN-2327) were studied in four beagle dogs after oral (2.5 mg/kg) and intravenous (0.5 mg/kg) administration of racemate in a two-way, crossover study design. Racemic pazinaclone was highly cleared after intravenous administration at 2.09 +/- 0.78 l hr-1 kg-1. The total clearance and volumes of distribution (Vc, V beta, and Vss) of (S)-pazinaclone were significantly lower than those of the antipode. The differences in disposition were consistent with stereoselectivity in protein binding, where the unbound fraction of (R)-pazinaclone was almost 5-fold greater than that of the (S)-enantiomer. Lower clearance and distribution for (S)-pazinaclone resulted in comparable elimination half-lives for the two enantiomers. As projected from the intravenous results, the firstpass metabolism of (S)- and (R)-pazinaclone on oral administration of racemic pazinaclone was very extensive and stereoselective, with mean bioavailabilities of 6.0 and 1.2%, respectively, but the rates of absorption of the enantiomers were similar. Simultaneous model-dependent analysis of the intravenous plasma profiles for parent drug and metabolite suggested stereoselectivity of the active metabolite MII with shorter formation half-life for (S)-MII. However, in vitro metabolism by liver slices and our in vivo data indicated exclusive elimination of (S)- and (R)-pazinaclone through complete conversion to the MII metabolite (fm = 1). Thus, the clearances of (S)- and (R)-MII were calculated to be 0.89 and 7.89 l hr-1 kg-1, respectively, indicating pronounced stereoselectivity in the metabolite clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗