Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally-induced renal impairment

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg^?1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K₁₂, K₁₂, K_a and an increase in V_d and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK₁₃ and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.     

HI-6 pharmacokinetics in rabbits after intravenous and intramuscular administration.

The pharmacokinetics of HI-6 ((4-carboxamidopyridinium (1) methyl)-(2'-hydroxyiminomethyl-pyridinium (1') methyl) ether dichloride) have been studied in rabbits receiving an intramuscular (50 micrograms kg-1) or intravenous (12.5 micrograms kg-1) dose. The plasma concentration-time profile for the intramuscular dose (n = 8) fits a one-compartment open model with first-order absorption and elimination. The absorption half-life was 2 min and maximum concentration (51 micrograms mL-1) was reached in 9 min. The pharmacokinetics for the intravenous dose (n = 8) was described by a two-compartment open model with first-order distribution and elimination. The apparent volume of distribution was 0.1 L kg-1. Half-lives of distribution and elimination were 5 and 38 min, respectively. The results indicate HI-6 is rapidly absorbed, distributed and eliminated in rabbits receiving an intramuscular dose.     

左氧氟沙星口服或静脉注射家兔泪液、角膜组织的药动学比较

目的家兔口服或静脉注射(静注)左氧氟沙星后泪液与角膜组织的药动学比较。方法选取54只家兔分成口服组和静注组(n=27),分别口服或静注左氧氟沙星24 mg·kg~(-1),不同时间采集泪液或角膜组织,高效液相色谱法测定药物浓度,3p97软件计算药动学参数。结果口服给药后泪液和角膜组织中左氧氟沙星t_(max)、c_(max)和AUC_(0-t)分别为(0.58±0.20)与(1.00±0.55)h、(34.27±11.69)与(8.51±2.72)μg·g~(-1)、(157.19±32.15)与(22.90±2.63)μg·h·g~(-1);静注后分别为(0.83±0.26)与(0.83±0.26)h、(30·44±3.18)与(6.12±0.71)μg·g~(-1)、(136.72±20.12)与(26.01±5.59)μg·h·g~(-1)。左氧氟沙星口服或静注给药后泪液和角膜组织间药物浓度和药动学参数均无显著差异(P>0.05)。结论左氧氟沙星口服和静注在家兔泪液和角膜组织中药动学参数相似。     

Boric acid single dose pharmacokinetics after intravenous administration to man

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cl_tot 54.6±8.0 ml/min/1.73 m², t_1/2 21.0±4.9 h and distribution volumes V₁, V₂, and V₃: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.     

Normal pharmacokinetics of 99mTc-diphosphonate after intravenous administration

In the past several years bone imaging has become a routine diagnostic tool for the nuclear medicine clinician. However, increased information may be derived by determinating the radio-pharmacokinetic parameters associated with blood, urine, and bone. In an adult male population of normals (N = 5–6) blood clearance, urinary excretion, and skeletal uptake of ^99mTc-Diphosphonate were determined as a function of time after intravenous (i.v.) administration. The quantitative imaging studies (lower lumbar region) were performed up to 1 h post administration with a scintillation camera interfaced to a computer. Blood levels exhibited a triexponential clearance pattern and urinary excretion of the radiopharmaceutical was essentially complete by 4 h. The computer-generated images showed an initial early uptake in bone, kidneys, and soft tissue. Thereafter, a parallel fall-off in activity was observed in kidneys and soft tissue, with a concomitant increase in bone.     

不同给药途径对家兔阿米卡星药动学参数的影响

目的 :研究肌注和鼻甲注射对家兔阿米卡星 (AMK)药动学参数的影响。方法 :8只家兔予AMK 4mg·kg-1,im ,2wk后再以鼻甲注射同等剂量的AMK ,分别于给药后不同的时间点取血。通过荧光偏振免疫法 ,测定AMK的血药浓度 ,获得不同的药动学参数。结果 :肌注和鼻甲注射AMK后 ,Ke ,cmax和AUC均无显著性差异 ,而Ka ,T1/2 (Ka) ,tmax均有显著差异 (P <0 0 0 1) ;但鼻甲注射方法的达峰浓度较肌注高。结论 :鼻甲注射AMK后吸收较肌注迅速 ,两者的消除相似     

Influence of severe renal impairment on the pharmacokinetics of clazosentan

The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (±10 years). The PK parameters of clazosentan were calculated by both model-independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-∞) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment.     

Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects

Summary To support the increasing use of intravenous -blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of ¹⁴C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml·min^–1), renal clearance (131 to 150 ml·min^–1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (V_ss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation (r ²=0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except V_ss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent.     

Dose-independent pharmacokinetics of torasemide after intravenous and oral administration to rats

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.     

Methylprednisolone pharmacokinetics after intravenous and oral administration.

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.     

Mammary excretion of cannabidiol in rabbits after intravenous administration

Abstract— The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg^?1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4–24-h period following the maternal injection. The mean milk to serum concentration ratio was 25·9, indicating a significant accumulation of the drug in milk.     

Phenytoin pharmacokinetics after intravenous administration to patients receiving enteral tube feeding

Serial plasma samples were collected after administration of 13 intravenous doses of phenytoin to 11 patients with head injury; 5 to patients who had been receiving enteral feeds for less than 5 days (group 1), and 8 to patients who had been receiving enteral feeds for longer than 5 days (group 2). Average plasma phenytoin concentrations were higher in group 1 than in group 2 (p=0.003). The median intravenous study dose was the same (300 mg) in both groups (p=0.1 7). Group 2 received slightly higher doses expressed as mg/kg (median of 5.45 mg/kg compared to 4.29 mg/kg in group 1, p=0.21). Phenytoin was more rapidly eliminated following intravenous dosing in patients receiving long-term enteral feeding.V _max was higher in group 2 than in group 1 (medians, 709versus 394 mg/day) andK _m smaller (medians, 2.5versus 3.9 mg/l), but volume of distribution was similar in both groups (p=0.88). The kinetic parameters of phenytoin in group 1 were similar to previously published population pharmacokinetic parameters. In order to maintain phenytoin concentrations adequate for seizure prophylaxis in patients receiving longterm enteral feeding it would be advisable to decrease the dosing interval as well as increasing the phenytoin dose when the drug is administered intravenously.     

The pharmacokinetics of methotrexate after intravenous administration of methotrexate-loaded proliposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX-loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg^?1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (C_p), the area under the plasma concentration-time curve (AUC, 639 versus 913 μg min mL^?1), the terminal half-life (t_1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (V_ss, 98.1 versus 2800 mL kg^?1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min^?1 kg^?1), renal clearance (CL_R, 4.49 versus 2.78 mL min^?1 kg^?1), non-renal clearance (CL_NR, 7.50 versus 5.99 mL min^?1kg^?1), and the amount of MTX excreted in urine (X_u, 808 versus 685 μg, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX-loaded liposomes (formed immediately after hydration of MTX-loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and V_ss from treatment II), and MTX is slowly released from MTX-loaded liposomes (higher t_1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher C_p and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t_1/2, MRT, and V_ss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX-loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX-loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX-loaded proliposomes when incubated with phosphate-buffered saline (PBS), rat plasma, or rat liver homogenate.     

Meloxicam pharmacokinetics in renal impairment

Aims The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment.
Methods Meloxicam was administered to subjects with mild (creatinine clearance 41–60 ml min⁻¹) to moderate (20–40 ml min⁻¹) renal impairment compared with normal renal function (>60 ml min⁻¹). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods.
Results Subjects with no or mild renal impairment showed sinular pharmacokinetic profiles (geometric mean AUC_SS (%gCV) 55 (33%) vs 55 (38%) μg ml⁻¹ h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUC_SS 35 (50%) μg ml ⁻¹ h, with corresponding higher plasma clearance ( P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups.
Conclusions On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.     

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (F_srr and F_rr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of F_srr (13.67%) and F_rr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine. Received: 23 July 1998 / Final version: 2 February 1999     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.