Pharmacokinetics of theophylline after administration of suppositories formulation

Asthma is a public health problem for developed countries. It attacks all age groups but often starts in childhood. Theophylline ethanoate of piperazine in a suppository form is one of the treatments of asthmatic children. The pharmacokinetics of theophylline were evaluated in 24 healthy male subjects after administration of theophylline ethanoate of piperazine suppositories (PR) (Minophylline 500 mg. Alexandria Co.) and single injection intravenous (IV) of theophylline ethanoate of piperazine (Minophylline ampoules 500 mg Alexandria Co.). The theophylline serum levels were determined by an ELISA method. Peak theophylline plasma concentration, Cmax, (mean +/- S.D) was 21.5 +/- 2.10 microg/mL & 14 +/- 0.90 microg/mL; AUC(0-t), values were 80.9 and 67. 4 microg x ml x hr for the reference IV preparation and suppositories, respectively. The median peak time, Tmax, was 0.5 hr for theophylline rectal administration. The above mentioned results demonstrate the possibilities of using theophylline (Minophylline Suppositories--500 mg Alexandria Co.) in asthmatic children in rural and desert areas away from health care personnel.     

Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration

The pharmacokinetics of ciprofloxacin was studied in three groups of healthy volunteers comprising a total of 16 males and 16 females (age 21–35 years; body weight 52–80 kg). Single oral doses of 50, 100, 250, 500 and 750 mg were given to fasting subjects. The 250 mg dose was repeated after a breakfast. Intravenous doses of 50, 100 and 200 mg were given by short infusion in a randomized cross-over sequence. Concentrations of the drug in serum and urine were determined by high-performance liquid chromatography and by a microbiological assay. Mean peak concentrations between 0.37±0.49 mg/l (100 mg dose) and 1.97±0.50 (750 mg dose) were measured 60–75 min after oral administration. Twelve hours after 750 mg ciprofloxacin, serum concentrations were 0.15±0.05 mg/l. Taking a breakfast reduced absorption by 15–20% compared to the fasting state, as judged by peak concentrations, AUC and renal excretion. After 200 mg i. v. (20 min infusion period), initial serum concentrations of 4.0±1.2 mg/l were observed which declined 12 h later to 0.070±0.025 mg/l. Mean cumulated recovery of ciprofloxacin from urine over 24 h varied between 25.5% and 33.6% of oral doses and between 53.2% and 57.4% of intravenous doses. Two of the three metabolites seen in the chromatograms were identified as M1 and M3 (oxo-ciprofloxacin). Cumulated renal excretion after an oral 250 mg dose was 1.2±0.4% of M1 and 5.5±1.6% of M3. Bioavailability of oral doses varied from 0.64±0.16 (100 mg) to 0.52±0.11 (500 mg). The AUC was linearly proportional to a single dose of up to 250 mg. Ciprofloxacin was rapidly absorbed and distributed. High distribution volumes were calculated (mean VD_area 186–217 1). The terminal half-life (t₁/2) was 3.1 to 5.4 h. Mean total body clearance was also high (600 to 693 ml/min · 70 kg)). Tolerance of ciprofloxacin was good for all oral doses and for intravenous administration up to 100 mg per dose. Intravenous infusion of 200 mg ciprofloxacin caused transient local irritation.     

Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers

The pharmacokinetics of ciprofloxacin (Bay o 9867) was examined after a single oral dose of 250 mg and a single intravenous dose of 100 mg respectively in six healthy male volunteers in an open, randomized crossover study. Although ciprofloxacin concentrations were measured in serum, plasma and urine by HPLC with fluorimetric detection and by microbiological assay, all pharmacokinetic calculations are based on the highly sensitive HPLC method only. The mean serum concentration of ciprofloxacin peaked approximately1 h after the oral dose (0.94 mg/l). The elimination half-life was about 4 h and the renal clearance was 4.75 ml/min·kg; both were independent of the route of administration. The total clearance (9.62 ml/min·kg) was about twofold higher than the renal clearance. The volume of distribution of the central compartment was calculated to be 0.16 l/kg and the total volume at steady state was 2.0 l/kg. About 27 % of the oral dose was excreted in urine, whereas the urinary recovery of the i.v. dose was 46 %. The absolute bioavailability of ciprofloxacin was found to be approximately 60 %. Ciprofloxacin appears to follow first-order, three compartment model kinetics.     

Pharmacokinetics of amoxicillin-clavulanic acid combination after intravenous and intramuscular administration to turkeys and chickens

The pharmacokinetic behaviour of amoxicillin/clavulanic acid (4:1) combination was studied after intravenous and intramuscular administration of single doses (25 mg/kg body weight) to 15 turkeys and 15 chickens. The objective was to determine whether there are differences between turkeys and chickens in the disposition kinetics of amoxicillin and clavulanic acid. The plasma concentrations-time data were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs after intravenous administration were best described by a two-compartment open model in turkeys and chickens. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. The body clearances of amoxicillin and clavulanic acid in turkeys were significantly slower than in chickens. The elimination half-life of amoxicillin was similar in turkeys (1.12 +/-0.09 h) and chickens (1.03 +/-0.11 h) after intravenous administration, but that of clavulanic acid differed significantly (P<0.05) between turkeys (1.12 +/-0.03 h) and chickens (0.98 +/- 0.05 h). After intramuscular administration both drugs had a significantly longer half-life (P<0.05) in turkeys and chickens than that after the intravenous treatment. The bioavailability after the intramuscular injection was high and similar with both drugs, but higher values were obtained for chickens than turkeys.     

Pharmacokinetics of an immunomodulator peptidoglycan monomer in mice after intravenous administration

A ¹⁴C labeled low molecular weight immunomodulator, peptidoglycan monomer (¹⁴C-PGM), was injected intravenously (i.v.) into mice. At various time intervals thereafter (15 min – 6 h), radioactivity in the urine, whole blood, plasma, kidneys, liver, spleen, lungs, intestines and the brain of the mice was determined. Shortly after injection, ¹⁴C-PGM was very rapidly excreted from the organism, so that 1 h following administration, 80% of the radioactivity was found in the urine (62% as unchanged PGM and the rest as the metabolites pentapeptide and disaccharide). At the same time, around 2% of the injected material was found in the blood. Six hours after injection, equal quantities were found in the intestines, liver and blood (0.5%), slightly less in the kidneys, lungs and spleen (0.2–0.3%) and the least quantity in the brain (0.04%). However, the dynamics of retention in the organs was evidently different. In the kidneys, lungs and spleen, radioactivity steadily decreased over the studied period. In the liver following an initial decrease, radioactivity remained the same 3 and 6 h after injection. On the other hand, in the intestines and brain PGM seemed to accumulate rather than disapper following i.v. administration. This fact should be considered when explaining different biological activities of low molecular weight bacterial peptidoglycans.     

Pharmacokinetics of oral and intravenous rifampicin during chronic administration

Summary We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic first-pass effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.Abbreviations AUC area under the serum concentration-time curve - Cl clearance - RMP rifampicin - t 1/2 half-life - Vd_area volume of distribution Dedicated to Professor Dr. Hans J. Dengler on the occasion of his 60th birthday     

Pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400 mg

PurposeTo investigate the pharmacokinetics and pharmacodynamics of ciprofloxacin in critically ill patients after the first intravenous administration of 400 mg.Material/methods.Plasma concentrations were measured in 20 critically ill patients (mean [SD]; age, 55.5 [16.5] years; weight, 80.3 [16.9] kg; and creatinine clearance, 110.0 [71.5] mL/min). Four blood samples were drawn at the following time points 0, 0.5, 6, 8 hours after infusion. Ciprofloxacin concentrations were determined by high-performance liquid chromatography. Results. In the cases where ciprofloxacin was applied in targeted antibiotic therapy the minimum inhibitory concentrations (MIC) were ≤0.5 mg/l. The maximum and minimum plasma concentrations of ciprofloxacin were 1.74 (0.58-7.90) and 0.45 (0.16-2.96) mg/l, respectively. The main pharmacokinetic parameters for ciprofloxacin in the analyzed patients were as follows: k_el, 0.21 h^?1; t_1/2kel, 3.37 h; AUC_0-inf, 10.10 mg×h/l; AUMC_0-last, 15.36 mg×h²/l; MRT, 1.71 h; V_d, 214.8 l; Cl, 39.70 l/h. Considering the maximum value of MIC (0.5 mg/l) only 30% and 25% of analyzed patients had desired values of the PK/PD indexes AUIC>125 and C_max /MIC>10, respectively.Conclusions.The target plasma concentrations after the first dose of ciprofloxacin were reached only in a few critically ill patients. Considerable inter-subject variability for PK/PD parameters in ICU patients requires systematic monitoring.     

Effect of serum caffeine level on pneumocardiogram of premature infants treated for apnea with theophylline

It is speculated that measurement of serum theophylline concentration alone, without concomitant caffeine level determination, may lead to a false negative (normal) pneumocardiogram due to possible existence of therapeutic caffeine level resulting from the methylation of theophylline. Treatment of neonatal apnea with theophylline as documented by a normal follow-up pneumocardiogram should be considered successful only when the levels of both theophylline and caffeine have been documented subtherapeutic at time of re-test.     

Pharmacokinetics of amixin after repeated peroral administration to mice

Pharmacokinetics of amixin was studied after repeated administration (5 days) to animals. Perorally administered amixin is characterized by high bioavailability and is present in the circulation in high concentrations for a long time. The main pharmacokinetic parameters were estimated by the method of linear regression because of slow elimination of amixin from organs and tissues. Our results indicate that repeated treatment with amixin holds much promise for the prevention and therapy of chronic diseases (particularly hepatitides). __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 140, No. 12, pp. 661–663, December, 2005     

Endocrinology: Pharmacokinetics of two human menopausal gonadotrophin preparations after single intravenous administration during pituitary suppression

A randomized study was performed in nine healthy women, to investigatepharmacokinetic parameters and bioequivalence of two human menopausalgonadotrophin preparations after i.v. administration. Endogenousgonadotrophin activity was suppressed by triptorelin administration.Humegon and Pergonal (225 IU of each) were injected i.v. ina cross-over way with an interval of 1 week. Blood samples werecollected frequently and serum concentrations of follicle stimulatinghormone (FSH), luteinizing hormone (LH), specific LH, and humanchorionic gonadotrophin (HCG) were determined by fluoroimmunoassaysassays. Serum LH bioactivity was measured by an in-vitro bioassay.The area under curve (AUC) and half-life of FSH were respectively431.5 IU h/1 and 22.20 h for Humegon, and 402.6 IU h/1 and 21.33h for Pergonal. For both preparations, the (total) LH immunoactivityand in-vitro bioactivity of serum LH were very similar, andappeared to be a composite of specific LH and HCG activity.The AUC data of specific LH were 17.50 IU h/1 for Humegon and21.79 IU h/1 for Pergonal respectively. The AUC and half-lifeof HCG were 153.7 IU h/1 and 14.80 h for Humegon, and 134.1IU h/1 and 12.11 h for Pergonal. The two preparations were bioequivalentwith respect to FSH and HCG immunoreactivity. Bioequivalencecould not be proven for LH activity because of the small numberof subjects.     

Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses

The pharmacokinetics of ciprofloxacin were evaluated after increasing single oral doses of 100, 250, 500 and 1000 mg, and an intravenous dose of 100 mg given to each of 12 healthy volunteers (6 females and 6 males). Concentrations in serum and urine were determined by microbiological assay. The rise in peak serum concentrations and the values of the total area under the serum concentration curve were proportional to the increase in the oral doses. As the oral dose increased a slight increase was observed in the apparent time lag before absorption from 0.34 h after 100 mg to 0.53 h after 1000 mg. The serum half-life after the intravenous dose was 3.2 h. After the oral doses shorter apparent half-life values were observed. The intravenous dose showed an elimination phase distribution volume of 2.76 l/kg and total body clearance of 40.7 l/h. The total urinary excretion was 42.2±15.6% of the dose after the intravenous dose; the figure was lower after the oral doses. The bioavailability of the 100 mg oral dose was 83.7% as calculated from the value of the total area under the serum curve after the same oral and intravenous dose in all 12 subjects. Ciprofloxacin thus demonstrates normal linear pharmacokinetics, the rise in serum concentrations being proportional to the dose.     

Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (相似文献   

On the mechanism of action of theophylline and caffeine

Important developments in our understanding of the mechanism of action of methylxanthines have taken place in the last 10 years. A brief overview of these developments is provided below and the author concludes that the common view that theophylline (and caffeine) acts by raising the levels of cyclic AMP is generally untenable. Instead, many of the actions of the methylxanthines can be explained on the basis of their being antagonists of endogenous adenosine. However, the mechanism behind the antiasthmatic effects of xanthines still remains unknown and further research is necessary.     

Distribution of adenoviral vector in brain after intravenous administration

The delivery of transgenes to the central nervous system (CNS) can be a valuable tool to treat CNS diseases. Various systems for the delivery to the CNS have been developed; vascular delivery of viral vectors being most recent. Here, we investigated gene transfer to the CNS by intravenous injection of recombinant adenoviral vectors, containing green fluorescence protein (GFP) as a reporter gene. Expression of GFP was first observed 6 days after the gene transfer, peaked at 14 days, and almost diminished after 28 days. The observed expression of GFP in the CNS was highly localized to hippocampal CA regions of cerebral neocortex, inferior colliculus of midbrain, and granular cell and Purkinje cell layers of cerebellum. It is concluded that intravenous delivery of adenoviral vectors can be used for gene delivery to the CNS, and hence the technique could be beneficial to gene therapy.     

Pharmacokinetics of oral theophylline in Thai asthmatic children

Pharmacokinetic studies of theophylline were carried out in 12 Thai asthmatic children after oral administration of Elixir Quibron and Tablet Aminophylline. No significant differences in any of the pharmacokinetic parameters between these two dosage forms were observed. Peak serum concentrations of theophylline were reached in an average time of 3.16 hours (range 1.71-7.71). It was shown that the elimination half-life of theophylline in Thai asthmatic children (average 7.21 hours) was longer than that observed for subjects in western countries. Variations in elimination half-lives ranging from 4.44 to 14.34 hours were intersubject variations. Due to the slow elimination of theophylline in Thai patients, a dosage regimen of 5 mg/kg every 8 hours was recommended as more suitable than 5 mg/kg every 6 hours. Using data from this study, the predicted maximum and minimum serum theophylline concentrations at steady state were calculated to be 16.53 micrograms/ml and 9.96 micrograms/ml, respectively. This dosage regimen should be suitable not only for Thai people but also for Asian people of similar races and under similar environmental conditions.