Steady-state Volume Of Distribution Research Articles

Pharmacokinetics and brain distribution of magnolol in the rat after intravenous bolus injection.

The pharmacokinetics of magnolol in rats was studied after 2, 5, or 10 mg/kg-1 intravenous bolus injection. Plasma concentration-time profiles of magnolol were fitted by a two-compartment open model. There were no significant differences in the elimination half-life, the total body clearance, steady-state volume of distribution, or mean residence time. The area under the plasma-time curve and area under the moment-time curve of magnolol appears to increase proportionally from a dose of 2 to 10 mg/kg-1. These results suggest that magnolol possess linear pharmacokinetics. Notwithstanding, brain concentration of magnolol showed no significant difference among various regions (cerebral cortex, olfactory bulb, hippocampus, striatum, cerebellum, brain stem and rest of brain) after 10 min of magnolol (5 mg/kg-1, i.v.) administration, the mean brain drug concentration was approximately fourfold that of magnolol in plasma.

Structure-pharmacokinetic Relationships among the N1, N3-Alkylxanthines in Rats

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1,N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P less than 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.

Differential effects of ketoprofen on the pharmacokinetics of sulphadimethoxine in fast and slow acetylator rabbits

Intravenously co-administered ketoprofen decreased the plasma concentration of sulpha-dimethoxine (SDM) after intravenous bolus administration to fast acetylator rabbits, and significantly increased the total body clearance (CLtot) and steady-state volume of distribution (Vdss) of SDM. On the other hand, ketoprofen had little effect on the plasma concentration of SDM in slow acetylator rabbits. When SDM was intravenously administered in combination with ketoprofen, an increase in the plasma concentration of N4-acetylsulphadimethoxine, a major metabolite of SDM that strongly displaces SDM from its binding sites, was observed in all rabbits, but the increase was much larger in fast acetylators. We conclude that the acetylation capacity for SDM is a factor determining the pharmacokinetic interaction between SDM and ketoprofen in rabbits.

Moment analysis for disposition kinetics of several cephalosporin antibiotics in rats.

Disposition kinetics of cefamandole, cefoperazone, cefotiam, cefmenoxime and cefmetazole following rapid intravenous injection into rats is investigated. The plasma concentrations of the antibiotics are determined by the high performance liquid chromatographic method, and the pharmacokinetic behaviours of the cephalosporins are evaluated by moment analysis which is a model-independent method. Analysis of variance (ANOVA) followed by the paired t-test reveals that cefmetazole and cefmenoxime have greater mean residence time (MRT) than cefotiam, cefamandole and cefoperazone, and that cefamandole and cefmetazole show larger steady-state volume of distribution (Vss) than the other cephalosporins. Cefamandole has the greatest total body clearance (40.2 ml kg-1 min-1) and cefmenoxime the smallest (7.72 ml kg-1 min-1).

The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats.

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.

Influence of a bacterial lipopolysaccharide on the pharmacokinetics of tobramycin in rats.

The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg-1) and inulin (100 mg kg-1) were administered intravenously 2 h after administration of 50, 250 or 500 micrograms kg-1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 micrograms kg-1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.

Determination of the steady-state volume of distribution using arterial and venous plasma data from constant infusion studies with procainamide.

Determination of the steady-state volume of distribution using arterial and venous plasma data from constant infusion studies with procainamide.

Pharmacokinetics and Pharmacodynamics of Mepolizumab, an Anti-Interleukin-5 Monoclonal Antibody

Mepolizumab is a fully humanized monoclonal antibody (IgG1/κ) targeting human interleukin-5 (IL-5), a key haematopoietin needed for eosinophil development and function. Mepolizumab blocks human IL-5 from binding to the α-chain of the IL-5 receptor complex on the eosinophil cell surface, thereby inhibiting IL-5 signalling. The pharmacokinetics of mepolizumab have been evaluated in clinical studies at doses of 0.05-10 mg/kg and at 250 mg, 750 mg and 1500 mg. Mepolizumab was eliminated slowly, with mean initial and terminal phase half-life values of approximately 2 and 20 days, respectively. Plasma clearance ranged from 0.064 to 0.163 mL/h/kg and steady-state volume of distribution ranged from 49 to 93 mL/kg. Pharmacokinetics were dose proportional and time independent. Estimates based on a two-compartment intravenous infusion model from patients with asthma or healthy subjects following single doses predicted mepolizumab plasma concentrations in multiple-dose studies involving patients with hypereosinophilic syndrome (HES), asthma or eosinophilic oesophagitis. The absolute bioavailability of mepolizumab was 64-75% following subcutaneous injection and 81% following intramuscular injection. Peripheral blood eosinophil levels decreased in healthy subjects and patients with HES, asthma, eosinophilic oesophagitis or atopic dermatitis after intravenous mepolizumab infusion and subcutaneous injection. Reductions in eosinophil counts in oesophagus, sputum, skin, bone marrow, nasal lavage fluid and/or bronchial mucosa after treatment with mepolizumab were observed in placebo-controlled studies in various indications. The relationship between percentage change from baseline in blood eosinophils and mepolizumab plasma concentrations was described by an indirect pharmacological response model. The estimated maximal decrease in eosinophil count was approximately 85% from baseline and the half-maximal inhibitory concentration (IC50) was approximately 0.45 μg/mL.

Pharmacokinetics of Intravenous CTLA4Ig (BMS‐188667) in Cynomolgus Monkeys Following Single and Multiple Doses

The pharmacokinetics of CTLA4Ig, a novel immunosuppressive therapeutic protein, were investigated in cynomolgus monkeys following intravenous administration of single and multiple doses of CTLA4Ig. In the single-dose study, two monkeys of each sex received a dose of either 10 or 33 mg kg−1 CTLA4Ig by an intravenous bolus injection into a saphenous vein. In the multiple-dose study, three monkeys of each sex received either 10, 22.4, or 50 mg kg−1 of CTLA4Ig as an intravenous bolus injection once every other day for 15 doses over 29 days. Serial blood samples were collected at appropriate time points following the single dose and the last multiple dose. The serum samples were analysed for CTLA4Ig using an enzyme immunoassay procedure. The serum concentration data were evaluated by a noncompartmental method. Following single and multiple doses, both peak plasma concentration (Cmax) and area under the curve (AUC) values for CTLA4Ig increased in a proportion comparable with the dose increment ratio. The clearance values (CLT) for CTLA4Ig were not altered following the administration of single doses. The terminal elimination half-life values (t1/2) showed a tendency to increase as the administered dose increased. The steady-state volume of distribution (VdSS) of CTLA4Ig was about 2–3 times the blood volume in monkeys. On the basis of the derived and simulated pharmacokinetic parameters (using superposition principles), it was concluded that the pharmacokinetics of CTLA4Ig was not altered by repeated dosing.

Pharmacokinetics of yohimbine following intravenous administration to horses

Yohimbine is an alpha 2 adrenergic receptor antagonist used most commonly in veterinary medicine to reverse the effects of the alpha 2 receptor agonists, xylazine and detomidine. Most notably, yohimbine has been shown to counteract the CNS depressant effects of alpha 2 receptor agonists in a number of species. The recent identification of a yohimbine positive urine sample collected from a horse racing in California has led to the investigation of the pharmacokinetics of this compound. Eight healthy adult horses received a single intravenous dose of 0.12 mg/kg yohimbine. Blood samples were collected at time 0 (prior to drug administration) and at various times up to 72 h post drug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC-MS) and data analyzed using both noncompartmental and compartmental analysis. Peak plasma concentration was 114.5 + 31.8 ng/mL and occurred at 0.09 + 0.03 h. Mean ± SD systemic clearance (Cls) and steady-state volume of distribution (Vdss) were 13.5 + 2.1 mL/min/kg and 3.3 + 1.3 L/kg following noncompartmental analysis. For compartmental analysis, plasma yohimbine vs. time data were best fitted to a two compartment model. Mean ± SD Cls and Vdss of yohimbine were 13.6 ± 2.0 mL/min/kg and 3.2 ± 1.1 L/kg, respectively. Mean ± SD terminal elimination half-life was 4.4 ± 0.9 h following noncompartmental analysis. Immediately following administration, two horses showed signs of sedation, while the other six appeared behaviorally unaffected. Gastrointestinal sounds were moderately increased compared to baseline while fecal consistency appeared normal.

Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids

The pharmacokinetics and analgesic effect of the nonsteroidal anti-inflammatory drug meloxicam (0.5 mg/kg) in goats were investigated. In a randomized, cross-over design the pharmacokinetic parameters were investigated in adult goats (n = 8) after single intravenous and oral administration. The analgesic effect was evaluated in kids using a randomized, placebo controlled and blinded protocol. Kids received meloxicam (n = 6) once daily and their siblings (n = 5) got isotonic NaCl intramuscularly while still anaesthetized after cautery disbudding and injections were repeated on three consecutive days. In the adult goats after intravenous administration the terminal half-life was 10.9 ± 1.7 h, steady-state volume of distribution was 0.245 ± 0.06 L/kg, and total body clearance was 17.9 ± 4.3 mL/h/kg. After oral administration bioavailability was 79 ± 19%, C(max) was 736 ± 184 ng/mL, T(max) was 15 ±5 h, although the terminal half-life was similar to the intravenous value, 11.8 ± 1.7 h. Signs of pain using a visual analogue scale were smaller in kids treated with meloxicam compared with kids treated with placebo on the first day after disbudding, but subsequently no difference in pain was noticeable. Plasma cortisol and glucose concentrations did not differ between the two groups.

Pharmacokinetics of a Florfenicol-Tylosin Combination after Intravenous and Intramuscular Administration to Beagle Dogs

A pharmacokinetic study of a commercial florfenicol-tylosin (2:1) combination product was conducted in six beagle dogs after intravenous (IV) and intramuscular (IM) administration at doses of 10 mg/kg (florfenicol) and 5 mg/kg (tylosin). Serum drug concentrations were determined by a validated high performance liquid chromatography (HPLC) using UV detection. A rapid and nearly complete absorption of both drugs with a mean IM bioavailability of 103.9% (florfenicol) and 92.6% (tylosin), prolonged elimination half-life, and high tissue penetration with steady state volume of distribution of 2.63 l/kg (florfenicol) and 1.98 l/kg (tylosin) were observed. Additional studies, including pharmacodynamic and toxicological evaluation are required before recommendations can be made regarding the clinical application of the product in dogs.

A Brief History of the Journal of Pharmaceutical Sciences' First 50 Years

A Brief History of the Journal of Pharmaceutical Sciences' First 50 Years

Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis

To investigate daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis to develop dosing recommendations. Prospective, open-label pharmacokinetic study. : Intensive care units located within a teaching medical center. Eight adults with known/suspected Gram-positive infections receiving continuous venovenous hemodialysis and daptomycin. Daptomycin at 8 mg/kg intravenously over 30 mins. Serial blood and effluent samples were collected over the next 48 hrs. Daptomycin protein binding was determined by equilibrium dialysis. Daptomycin continuous venovenous hemodialysis transmembrane clearance was determined by dividing daptomycin effluent by serum concentrations and multiplying by mean effluent production rate for each subject. Equations describing a two-compartment, open-pharmacokinetic model were fitted to each subject's daptomycin concentration-time data and pharmacokinetic parameters were determined by standard methods. Serum concentration-time profiles were simulated for two daptomycin regimens (8 mg/kg every 48 hrs and 4 mg/kg every 24 hrs). A total of 7.7 ± 0.6 mg/kg (mean ± sd) of daptomycin was administered, resulting in an observed peak concentration of 81.2 ± 19.0 μg/mL. Daptomycin steady-state volume of distribution (0.23 ± 0.14 L/kg) and free fraction (17.5% ± 5.0%) were increased in critically ill subjects receiving continuous venovenous hemodialysis compared with previous values reported in healthy volunteers. Daptomycin transmembrane clearance (6.3 ± 2.9 mL/min) accounted for more than half of total clearance (11.3 ± 4.7 mL/min). Simulations demonstrated 8 mg/kg daptomycin every 48 hrs would result in higher peak (88.8 ± 20.0 μg/mL vs. 53.0 ± 12.3 μg/mL) and lower trough concentrations (7.2 ± 5.2 μg/mL vs. 12.3 ± 5.1 μg/mL) than 4 mg/kg every 24 hrs. Daptomycin at 8 mg/kg every 48 hrs in critically ill patients receiving continuous venovenous hemodialysis resulted in good drug exposure, achieved high peak concentrations to maximize daptomycin's concentration-dependent activity, and resulted in trough concentration that would minimize the risk of myopathy. CLINICALTRIALS.GOV IDENTIFIER: NCT00663403.

Abstract P3-14-22: Pharmacokinetics (PK) of Trastuzumab-DM1 (T-DM1) and Paclitaxel (T) in Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with a Trastuzumab-Containing Regimen

Abstract Background T-DM1 is an antibody-drug conjugate composed of DM1 conjugated to trastuzumab. T-DM1 combines the antitumor properties of trastuzumab with the antimicrotubule activity of DM1. Nonclinical data suggest synergy for the combination of T-DM1 and taxanes. T-DM1 is expected to undergo proteolytic degradation with no significant involvement of cytochrome P450 isoenzymes (CYPs). DM1 is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. T is metabolized primarily by CYP2C8 and to minor metabolites by CYP3A4. Neither DM1 nor T inhibit or induce CYPs at clinically relevant concentrations. Since T and DM1 are substrates of CYPs, their PK may be altered by interaction with other compounds that are substrates, inhibitors or inducers of CYPs. Given these metabolic pathways, it is important to evaluate if a PK-based drug-drug interaction potential exists when T-DM1 and T are administered together. Methods The tolerability, PK and dose-limiting toxicities of T-DM1 (q3w and qw) and T (qw) (and pertuzumab in subsequent cohorts) in patients with HER2- positive MBC previously treated with a trastuzumab-containing regimen were investigated in this 3+3 phase Ib study, TDM4652g. In Part 1, patients received T-DM1 (2.4 mg/kg or 2.0 mg/kg q3w) and T (65 mg/m2 or 80 mg/m2 qw). In Cycle 1 of all cohorts there was a planned 1-day delay between T and T-DM1 administration; in later cycles, T was administered immediately after T-DM1, allowing within study PK comparisons of T ± T-DM1. Study patients were evaluated for serum concentrations of T-DM1, total trastuzumab (conjugated and unconjugated to DM1), and plasma concentrations of DM1 and T, at prespecified time points. PK of T-DM1 and related analytes were compared to historical monotherapy data by population analysis and/or noncompartmental analysis (NCA). Whether combination with T was a significant covariate of T-DM1 clearance (CL) and central volume of distribution (V1) was tested. PK parameters of T at Cycle 1 (without T-DM1) and Cycle 2 (with T-DM1) were estimated and compared by NCA. Results from 14 patients enrolled in Part 1 are reported here. Results The maximal concentration (Cmax) and area under the concentration-time curve (AUC) values (days 0-7) of T-DM1 in combination treatment were comparable with historical monotherapy data (Table 1) as was the PK of total trastuzumab and DM1. Maximum DM1 level was <5 ng/mL. Combination with T was not a significant covariate of T-DM1 CL and V1 (p>.05, by log likelihood ratio test). The PK for T was comparable from Cycle 1 (without T-DM1) and Cycle 2 (with T-DM1) for Cmax, AUC, half-life, CL and steady-state volume of distribution. Conclusions This assessment suggests a low potential for PK-based T-DM1 T interaction when these drugs are given in combination therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-22.

Pharmacokinetics and Pharmacodynamics of Single Rising Intravenous Doses (0.5 mg–10 mg) and Determination of Absolute Bioavailability of the Dipeptidyl Peptidase-4 Inhibitor Linagliptin (BI 1356) in Healthy Male Subjects

Linagliptin (BI 1356) is a highly specific inhibitor of dipeptidyl peptidase (DPP)-4, which is currently in phase III clinical development for the treatment of type 2 diabetes mellitus. Linagliptin exhibits nonlinear pharmacokinetics after oral administration, which are mainly related to concentration-dependent binding of linagliptin to its target, DPP-4. The objectives of the study were to investigate the pharmacokinetics and pharmacodynamics after intravenous administration of linagliptin and to determine its absolute bioavailability (F). This was a single rising-dose, randomized, four-group, placebo-controlled, single-blind (within dose groups) study. Thirty-six healthy men aged 18-50 years were enrolled and randomized into four sequential treatment groups. Group 1 received linagliptin 0.5 mg intravenously, group 2 received 2.5 mg intravenously and group 4 received 10 mg intravenously. In group 3, subjects underwent a two-way randomized crossover, receiving 5 mg intravenously and a 10 mg oral tablet. Linagliptin concentrations in plasma and urine, as well as plasma DPP-4 activity, were determined by validated assays. Noncompartmental analysis and population pharmacokinetic modelling were performed. Linagliptin showed nonlinear pharmacokinetics after intravenous infusion of 0.5-10 mg, with a less than dose-proportional increase in exposure. Noncompartmental parameters were calculated on the basis of total (i.e. bound and unbound) plasma concentrations. The total clearance value was low and increased with dose from 2.51 to 14.3 L/h. The apparent steady-state volume of distribution (V(ss)) increased with dose from 380 to 1540 L. Renal excretion of the unchanged parent compound increased with increasing plasma concentrations from 2.72% in the 0.5 mg dose group to 23.0% in the 10 mg dose group. The terminal elimination half-life was comparable across dose groups (126-139 hours). Because of the nonlinear pharmacokinetics, the standard approach of comparing the area under the plasma concentration-time curve (AUC) after oral administration with the AUC after intravenous administration led to dose-dependent estimates of the absolute bioavailability. Therefore, a population pharmacokinetic model was developed, accounting for the concentration-dependent protein binding of linagliptin to its target enzyme, DPP-4. The model-derived estimates of the V(ss) and clearance of linagliptin not bound to DPP-4 were 402.2 L and 26.9 L/h, respectively. The absolute bioavailability was estimated to be about 30% for the linagliptin 10 mg tablet. The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.

An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic

Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram-positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function.Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t1/2]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values.Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half-lives between 1.2 and 2.4 h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys.Application of the simple allometric equation (Y = aWb) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl × BW = aWb) resulted in a good correlation between predicted and observed values of Cl, AUC, and t1/2 in humans.These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans.

Pharmacokinetic–pharmacodynamic integration of orbifloxacin in Japanese quail (Coturnix japonica) following oral and intravenous administration

The pharmacokinetics of single-dose administration of orbifloxacin were determined in Japanese quail (Coturnix japonica) at dosages of 5 mg/kg intravenous (i.v. n = 12) and 7.5 mg/kg oral (p.o.; n = 5), 10 mg/kg p.o. (n = 5), 15 mg/kg p.o. (n = 12) and 20 mg/kg p.o. (n = 5) via HPLC. Orbifloxacin minimal inhibitory concentrations (MICs) against 22 microbial isolates from various bird species were performed to calculate pharmacodynamic surrogate markers. The concentration-time data were analyzed using a naïve pooled data (NPD) approach and compartmental and noncompartmental methods. Steady-state volume of distribution (Vd(ss)) and total body clearance (Cl) after i.v. administration were estimated to be 1.27 L/kg and 0.60 L/h·kg, respectively. Following 15 and 20 mg/kg p.o. dose, bioavailability was 102% and 117%, respectively. The harmonic mean of the corresponding terminal half-lives (T(1/2) λ(z) ) across all the dose groups was 1.71 h. The C(max) /MIC(90) and AUC(0∞24) /MIC(90) for the 15 and 20 mg/kg p.o. doses were ≥5.22 and ≥8.98, and ≥25.80 and ≥39.37 h, respectively. The results of this study suggest that 20 mg/kg orbifloxacin p.o. would be a rational daily dose to treat susceptible infections in Japanese quail not intended for food consumption. For more sensitive bacterial organisms, 15 mg/kg p.o. may also be effective.

A possible mechanism for the decrease in serum thyroxine level by phenobarbital in rodents

Effects of phenobarbital (PB) on the levels of serum thyroid hormones such as total thyroxine (T 4) and triiodothyronine were examined in male mice, hamsters, rats, and guinea pigs. One day after the final administration of PB (80 mg/kg, intraperitoneal, once daily for 4 days), significant decreases in the levels of the serum total T 4 and free T 4 occurred in mice, hamsters, and rats, while a significant decrease in the level of serum triiodothyronine was observed in hamsters and rats among the animals examined. In addition, a significant decrease in the level of serum thyroid-stimulating hormone was observed in only hamsters among the rodents examined. Significant increases in the level and activity of hepatic T 4-UDP-glucuronosyltransferase (UGT1A) after the PB administration occurred in mice, hamsters, and rats, while the increase in the amount of biliary [ 125I]T 4-glucuronide after an intravenous injection of [ 125I]T 4 to the PB-pretreated animals occurred only in rats. In mice, rats, and hamsters, but not guinea pigs, PB pretreatment promoted the clearance of [ 125I]T 4 from the serum, led to a significant increase in the steady-state distribution volumes of [ 125I]T 4, and raised the concentration ratio (Kp value) of the liver to serum and the liver distribution of [ 125I]T 4. The present findings indicate that the PB-mediated decreases in the serum T 4 level in mice, hamsters, and rats, but not guinea pigs, occur mainly through an increase in the accumulation level of T 4 in the liver.

Cefuroxime Pharmacokinetics in Pediatric Cardiovascular Surgery Patients Undergoing Cardiopulmonary Bypass

The objective of this study was to determine the pharmacokinetics of cefuroxime in children undergoing cardiopulmonary bypass (CPB) for cardiovascular surgery. A prospective study. A tertiary pediatric teaching hospital. Infants and children undergoing CPB were enrolled in the study. An initial dose (mean, 24.2 ± 1.6 mg/kg) of cefuroxime was administered before surgical incision, and a second dose (mean, 14.4 ± 7.9 mg/kg) was administered in the CPB prime solution. Serial blood samples were obtained before, during, and after the CPB process. Samples were shipped on dry ice to the analytic laboratory and concentrations determined by a validated high-performance liquid chromatography method. A 2-compartment pharmacokinetic model was fitted to the data using maximum a priori-Bayesian estimation, with weight as a covariate. Monte Carlo simulations of a single-dose (25 mg/kg pre-CPB) approach and a 2-dose (25 mg/kg pre- and 12.5-mg/kg prime solution dose) approach were performed. Fifteen subjects (9 males/6 females) were enrolled in the study, with median (range) age and weight of 11 (3-34) months and 9.5 (4.5-15.4) kg, respectively. The median (range) duration of CPB was 136 (71-243) minutes. Median and range cefuroxime pharmacokinetic parameters were as follows: maximum concentration (Cmax) dose, 1: 328 (150-512) μg/mL; systemic clearance, 0.050 (0.041-0.058) L/h/kg; steady-state volume of distribution, 0.213 (0.081-0.423) L/kg; volume of distribution in the central compartment, 0.081 (0.046-0.162) L/kg; and elimination half-life, 3.76 (1.03-6.81) hours. The median 8-hour post-dose-simulated cefuroxime concentrations were 26.5 and 16.0 mg/L for the 2-dose and single-dose regimens, respectively. Manufacturers recommend that pediatric doses of cefuroxime (25-50 mg/kg) can be used in infants and children undergoing CPB to maintain adequate serum concentrations for surgical-site infection prophylaxis. A second intraoperative dose, administered through the CPB circuit, provides no additional prophylactic advantage.