Influence of experimentally induced fever on the disposition of cefpirome in buffalo calves

The influence of Escherichia coli endotoxin-induced fever on the disposition of cefpirome was investigated in five male buffalo calves following a single intravenous dose of 10mgkg(-1). Blood samples were collected from 1min to 24h of drug administration. The drug concentration in plasma was estimated by microbiological assay using E. coli as a test organism. The disposition of cefpirome followed two-compartment open model and the drug was detected above the minimum inhibitory concentration in plasma up to 12h. The Vd(area) and AUC were 0.75±0.01Lkg(-1) and 35.1±0.46μgml(-1)h, respectively. The elimination half-life of 1.81±0.009h and Cl(B) of 0.29±0.004Lkg(-1)h(-1) reflected rapid elimination and body clearance of cefpirome in febrile buffalo calves. Based on the results, a satisfactory dosage regimen of cefpirome in febrile buffalo calves was calculated to be 6mgkg(-1) to be repeated at 8h intervals.     

Comparative effects of cefpirome (HR 810) and other cephalosporins on experimentally induced pneumonia in mice

The chemotherapeutic efficacy of cefpirome (HR 810), a new polar aminothiazolylcephalosporin and that of ceftazidime, cefotaxime, cefoperazone, latamoxef and cefodizime were examined against experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. When compared in terms of MIC values against the infecting organism and the pharmacokinetic pattern, cefpirome showed equal activity and a similar pharmacokinetic behavior to ceftazidime and cefotaxime in mice. Trials to assess the bactericidal activity in vivo, however, showed that cefpirome displayed a more marked bactericidal effect in pneumonic mice than the other cephalosporins tested. Only cefodizime, a cephalosporin with extremely high and prolonged blood and tissue levels in experimental animals exerted chemotherapeutic effects similar to cefpirome. After cefpirome or cefodizime medication (50 mg/kg), the viable counts in the lungs of experimental animals fell steadily to 1/10,000 of the pretreatment level and, in contrast to the reference compounds, no regrowth of the challenge organisms could be observed with both drugs. Moreover, with ED50s ranging from 1.1 to 59.1 mg/kg in treatment studies, cefpirome as well as cefodizime were two to ten times more effective than ceftazidime and cefotaxime, whereas cefoperazone and latamoxef were considerably less effective.     

Influence of experimentally induced cholestasis on the pharmacokinetics of cefotiam

The pharmacokinetics of (7 beta-[2-(2-amino-thiazol-4-yl) acetamido]-3-[[1-(2-dimethylaminoethyl)-1H-tetrazol- 5-yl]thio)methyl)-ceph-3-em-4-carboxylic acid (cefotiam) was studied in rabbits with normal and experimentally decreased or annulled biliary excretion. The latter two states were induced by administration of 17 beta-estradiol and by tying of the choledochus, respectively. All animals included in the study received a single i.v. bolus type injection of 40 mg/kg of the antibiotic. The average values of the pharmacokinetic parameters obtained after such administration to the control rabbits, with normal biliary excretion, expressed in accordance with a two-compartment open kinetic model were: alpha = 15.598 h-1; beta = 2.717 h-1; K12 = 5.247 h-1; K21 = 7.093 h-1 and K13 = 5.975 h-1. Cholestasis modifies the parameters defining the distribution and elimination of cefotiam to a considerable extent. The serum half-life of the slow elimination phase had an average value of 0.116 h in the control group and 0.207 h in the group with mechanically induced cholestasis. Chemically induced cholestasis caused a lesser increase in the serum half-life.     

Effect of diacetylmonoxime on blood enzymes in fenitrothion-dosed buffalo calves

The effect of iv diacetylmonoxime (DAM) alone or in combination with atropine was determined on blood enzymatic activities in fenitrothion-exposed buffalo calves. Fenitrothion given po at 435 mg/kg bw produced pronounced inhibition of blood acetylcholinesterase (AChE) and elevation in serum aspartate and alanine aminotransferases, acid and alkaline phosphatases, and lactate dehydrogenase within 30 min. The administration of DAM alone or in combination with atropine significantly reactivated AChE activity. The administration of DAM + atropine decreased serum aspartate and alanine aminotransferase enzymes within 1-3 d. The reversal effect of DAM + atropine on serum phosphatases and lactate dehydrogenase was greater than that of DAM or atropine alone.     

Pharmacokinetics of aditoprim and trimethoprim in buffalo calves

Pharmacokinetic parameters of two antifolates, trimethoprim and aditoprim, were studied in buffalo calves. The elimination half-life of aditoprim (6.14 h) was nearly twice as long as that of trimethoprim (3.08 h) and compares well with values observed in heifers. This longer half-life of aditoprim is a result of its much larger distribution volume (four to five times larger) because the clearance of aditoprim was about twice as high as that of trimethoprim. The longer half-life of aditoprim is expected to give a longer duration of in vivo bacteriostatic activity than that of trimethoprim.     

Selenium toxicokinetics after oral and intravenous administration in buffalo calves

The blood levels, toxicokinetics and urinary excretion of selenium were investigated in healthy male buffalo calves after single oral and intravenous administration of selenourea at the dose rate of 0.75mg/kg (providing 0.48mg/kg selenium). The concentration of selenium in blood and urine was estimated spectrophotometrically. Following administration of the drug, the blood selenium disposition patterns exhibited two distinct peaks. The toxicokinetic parameters of selenium were determined by employing non-compartmental analysis. The values of AUC, t(1/2elm), Cl(B) and Vd(SS) were 18.46μgml(-1)h, 10.33h, 20.04mlkg(-1)h(-1)and 0.3lkg(-1), respectively, after oral administration and 23.97μgml(-1)h, 7.12h, 20.53mlkg(-1)h(-1) and 0.2lkg(-1), respectively, following intravenous injection of selenourea. The value of MRT was higher after oral dosing. The bioavailability of selenium, following oral administration of selenourea was 77%. Approximately, 22% of the total intravenous dose and 5.9% of total oral dose of selenium was excreted in urine within 24h of administration of selenourea. The data on blood Se levels may be of help in diagnosing the impeding selenium toxicosis and thus preventing mortality due to selenium toxicity.     

The effect of fever on quinine and quinidine disposition in the rat.

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.     

Influence of obesity on drug disposition

Physiologic changes associated with obesity and their effects on the distribution, protein binding, metabolism, and renal excretion of drugs are described. Changes in the volume of distribution correlate with drug lipophilicity. Drugs that have a high affinity for adipose tissue have an increased volume of distribution, whereas the distribution of drugs that have low partition coefficients is not altered substantially. Albumin and total protein concentrations are comparable in lean and obese subjects, but concentrations of alpha 1-acid glycoprotein are increased. Consequently, protein binding of acidic drugs is unchanged, but the free fraction of basic drugs may be decreased. Changes in hepatic drug clearance are complex. Phase 1 reactions and acetylation, a Phase 2 reaction, appear to be unaffected by obesity, but activity of Phase 2 glucuronidation and sulfation pathways is enhanced. Available physiologic and pharmacokinetic data on the effect of obesity on systemic clearance of highly extracted drugs are conflicting. Both glomerular filtration and tubular secretion appear to be increased in obese individuals, and tubular secretion may be disproportionately increased compared with filtration. Clearance of drugs that depend on glomerular filtration for elimination is consistently higher in obese subjects. Differences among patient populations, other conditions associated with obesity, and the small study populations described to date may account for some discrepancies in reported results. Awareness of the physiologic effects of obesity is essential for ensuring appropriate drug therapy in obese patients.     

Propranolol in experimentally induced stress

The beta-adrenergic receptor-blocking drug, d,l-propranolol, was compared with placebo for relief of experimentally induced anxiety. Subjects were chosen on the basis of having high levels of trait anxiety. Stress was induced experimentally by two performance tests. Single 40-mg doses of propranolol significantly slowed the heart rate, suggesting a satisfactory pharmacologic effect of the drug. The treatment was not superior to placebo, however, on any other measure. The experimental model used had clearly demonstrated an antianxiety effect of single 5-mg doses of diazepam. Propranolol at the dose used had little effect on psychic anxiety as determined by this model.     

The influence of 2,3-butanedione monoxime on dichlorvos-induced enzymatic changes in buffalo calves.

The effects of administration of 2,3-butanedione monoxime (2,3-BM) or atropine alone and in combination were determined on the blood enzymatic activities of dichlorvos-exposed buffalo calves. Dichlorvos given po at 160 mg/kg body weight produced pronounced inhibition of erythrocyte acetylcholinesterase (AChE) and elevation in serum aminotransferases and phosphatases within 30 min. 2,3-BM administered alone or in conjunction with atropine to dichlorvos-exposed calves significantly reactivated erythrocyte AChE activity whereas atropine was ineffective. The effect of 2,3-BM plus atropine on other enzymatic activities was comparatively greater than that of either drug alone. The results indicated that combined treatment with 2,3-BM and atropine was most effective in reversing dichlorvos-induced enzymatic alterations.     

Influence of water deprivation on the disposition of paracetamol

The effect of acute (96 h) water deprivation on the disposition of paracetamol (acetaminophen) has been examined in male Sprague-Dawley rats. Plasma and urinary concentrations of the drug and its two major metabolites, the glucuronide and sulphate, were determined by a sensitive and specific high performance liquid chromatographic assay. Following an intravenous dose of 100 mg kg-1 of paracetamol, no significant changes were found in the elimination rate constant (k), the mean residence time (MRT), total plasma clearance (Cl) and the apparent volume of distribution at steady-state (Vss). However, rats deprived of water for 96 h excreted a larger percentage of the administered dose as the glucuronide conjugate (15.3 vs 7.9%) and a smaller percentage as unchanged paracetamol (7.3 vs 20.7%) in the urine. In addition, there was a significant two-fold increase in the partial metabolic clearance to paracetamol glucuronide. Water deprivation also led to a significant reduction in the renal clearance of paracetamol accompanied by an increase in the renal clearance of the glucuronide.     

Clinical studies on cefpirome in pediatrics

Cefpirome (CPR, HR 810) was given intravenously to 10 children with acute bacterial infections including 8 with acute pneumonia, 1 each with acute pleuritis and urinary tract infections. Good to excellent clinical responses were obtained in all of the 10 patients and bacterial eradication were obtained for all 8 strains found in these cases. Slight elevation of GOT, GPT and eosinophilia were observed in 1 case each. From the above clinical results, it appears that CPR is a useful antibiotic for treatment of pediatric patients with various bacterial infections.     

Influence of obesity on sulfonamide disposition in Zucker rats

The genetically obese Zucker rat was used as a model of obesity and compared to its lean littermate to assess and quantify obesity-altered changes in the in vivo disposition of six sulfonamides. Body composition determination indicated that the obese rats were twice the weight of lean rats and a distinct trend towards an increase in fat free mass and total body water was observed. The sulfonamide blood concentration was measured by colorimetry after a 7 mg/kg intravenous dose. All sulfonamides exhibited a biexponential decline of blood concentration with time. The volume of distribution and clearance of sulfanilamide in lean and obese rats were similar resulting in similar elimination half-lives. A decrease in clearance coupled with a trend towards an increase in volume of distribution prolonged the elimination half-life of sulfadiazine in obese rats. For sulfapyridine, sulfamerazine, sulfisomidine and sulfisoxazole, increases in the volumes of distribution and clearances resulted in similar elimination half-lives in lean and obese rats. The free fractions of the sulfonamides were significantly increased in the serum of obese rats, the influence of which on the volume of distribution and clearance is discussed.     

Influence of advanced age on the disposition of acetazolamide.

The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly healthy volunteers, each of whom received an intravenous bolus dose of 5 mg/kg. The concentration time profile of AZ was determined in plasma, plasma ultrafiltrate, erythrocytes and urine. While the mean area under unbound plasma concentration-time curves was 81% higher in elderly subjects, areas based on total drug concentrations were similar in both groups. The mean renal plasma clearance was similar in both groups. The mean renal plasma clearance was similar between young and old for total AZ, but was significantly lower in the elderly for unbound drug (8.88 ml min-1 kg-1 vs 15.7 ml min-1 kg-1). Renal clearance of unbound AZ correlated well with creatinine clearance (r = 0.846, P less than 0.01). Peak erythrocyte levels were 45% higher in the elderly group (37.2 micrograms/ml vs 25.3 micrograms/ml) and were paralleled by a 46% increase in the mean area under the erythrocyte concentration-time curve for this age group. The unbound fraction of AZ in plasma was significantly greater in elderly than younger subjects (6.9 vs 4.1%, P less than 0.05). Integrated AZ erythrocyte concentrations correlated positively with AZ free fraction in plasma and inversely with its unbound renal clearance. These observed differences in AZ disposition between elderly and young have served to clarify host factors which may importantly influence susceptibility to adverse effects.     

Influence of gender on the disposition of cefotaxime and desacetylcefotaxime

The pharmacokinetics of cefotaxime and desacetylcefotaxime were evaluated in 11 female and 13 male subjects with end-stage renal disease. Subjects received single 1- or 2-g intravenous doses of cefotaxime sodium. Serum, urine, and dialysate concentrations of cefotaxime and desacetylcefotaxime were determined using high performance liquid chromatography. The results indicate that gender has no clinically significant influence on the disposition of cefotaxime or its active metabolite desacetylcefotaxime.     

Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers

AIMS: To determine the influence of age on the enantioselective disposition of ibuprofen in humans. METHODS: Healthy young (n = 16; aged 20-36 years) and elderly (n = 16; aged 66-84 years) volunteers were given a 400-mg oral dose of racemic ibuprofen, and blood and urine samples were collected for 24 h post drug administration. Serum concentrations, total and free, and urinary excretion of both enantiomers of ibuprofen together with the urinary excretion of the stereoisomers of the two major metabolites of the drug, both free and conjugated, were determined by high-performance liquid chromatography. RESULTS: Ageing had little effect on the distribution and metabolism of R-ibuprofen, unbound clearance of the R-enantiomer via inversion being approximately two-fold that via noninversion mechanisms in both age groups. In contrast, the free fraction of S-ibuprofen was significantly greater [33%; young 0.48 +/- 0.10%; elderly 0.64 +/- 0.20%] mean difference -0.16; 95% confidence interval (CI) -0.05, -0.27; P < 0.01; and the unbound clearance of the drug enantiomer was significantly lower (28%; young 15.9 +/- 2.2 l min-1; elderly 11.5 +/- 4.1 l min-1; mean difference 4.4; 95% CI 2.12, 6.68; P < 0.001) in the elderly. The metabolite formation clearances of S-ibuprofen via glucuronidation, and oxidation at the 2- and 3- positions of the isobutyl side chain decreased by 24, 28 and 30%, respectively, in the elderly compared with the young, the differences between the two age groups being significant in each case (P < 0.05). CONCLUSIONS: Following administration of racemic ibuprofen age-associated stereoselective alterations in drug disposition have been observed, with the elderly having increased free concentrations and lower unbound clearance of the S-enantiomer in comparison with the young. In contrast, the handling of the R-enantiomer is essentially unaltered with age. The results of this study indicate that the elderly have an increased exposure to the active ibuprofen enantiomer and thus some caution may be required when using this drug in this age group.     

Influence of short-term water deprivation on antipyrine disposition

The effects of acute (96 h) water deprivation on the disposition kinetics of antipyrine and hepatic cytochrome P-450 content were investigated in male rats. The disposition kinetics of antipyrine in rats deprived of water for 96 h was altered significantly: the total body clearance and steady-state volume of distribution decreased by 27.1 and 22.4%, respectively, as compared to control rats. There was no significant change in the disposition rate constant as a result of simultaneous changes in the volume of distribution and clearance. There was a 51.4% decrease in the hepatic cytochrome P-450 content in water-deprived rats. These results suggest that the pharmacokinetic changes observed in acute water deprivation with a model drug, antipyrine, are related to a decrease in total body water and to a reduced amount and/or activity of the hepatic microsomal oxidative enzymes.