Mean Elimination Rate Constant Research Articles

Pharmacokinetic Evaluation of Paclitaxel in South Indian Cancer Patients: A Prospective Study

Paclitaxel is a promising drug in the treatment of different solid tumors. It exhibits nonlinear pharmacokinetics, particularly when administered as a constant rate infusion for shorter duration (e.g., 3 h). Because of the nonlinearity, relatively small changes in dose may lead to large changes in peak plasma concentration and total drug exposure. The study was conducted to evaluate the pharmacokinetics of different doses of paclitaxel administered intravenously as an infusion. A prospective study was conducted in 23 cancer patients aged between 28 and 74 years, treated with paclitaxel (130, 200, 230, and 260 mg/m2) over 3 h as constant rate infusion. Plasma samples were collected from all patients at 0, 1, and 3 h and for five patients at 5 and 13 h and paclitaxel concentrations were determined using high-performance liquid chromatography method. The overall mean clearance was found to be 47.5847 ± 142.028 l/h; the mean volume of distribution was 142.028 ± 73.438 l; mean elimination rate constant was 0.336 ± 0.002/h; mean half-life was 2.086 ± 0.009 h; mean area under the curve (AUC) was 5.5917 ± 2.707 mg/ml*h; and the mean of mean residence time was 2.980 ± 0.0131 h. Paclitaxel showed nonlinear kinetics and the pharmacokinetic parameters calculated were similar to those quoted in the literature. The peak plasma concentration at 130 mg dose level was 2 μ/ml, but an increase in dose was not associated with proportional increase in plasma concentration. No significant difference was found between pharmacokinetic parameters such as clearance, volume of distribution, and AUC at different dose levels.

Accumulation of nifedipine after multiple doses.

The single and multiple dose pharmacokinetics of oral nifedipine capsules, 10 mg, have been examined in five patients with peripheral vasospasm. After a single dose, nifedipine was rapidly absorbed in three and slowly absorbed in two patients. Mean bioavailability parameters included a tmax of 2.9 h, a Cmax of 33.3 ng ml-1 and a AUC0-8 h of 113.3 ng h ml-1. After multiple dosing with either 10 or 20 mg every 8 h for 10 days the mean tmax at steady state was 2.1 h while the mean dose-corrected (to 10 mg) Cmax and AUC0-8 h were 51.9 ng ml-1 and 146.9 ng h ml-1, respectively. The mean elimination rate constant was 0.173 h-1 after both single and multiple doses. The mean extent of accumulation of nifedipine, defined as the ratio of AUC0-8 h (steady state)/AUC0-8 h (single dose), was 1.3; we concluded that nifedipine accumulates in the body when it is administered every 8 h. This should be taken into account when predicting steady state serum concentrations and haemodynamic effects of nifedipine from single dose kinetic data.

CYP3A4 Genetic Polymorphism Influences Repaglinide’s Pharmacokinetics

Aim: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide’s pharmacokinetics in healthy Malaysian subjects. Methods: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. Results: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide’s blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide’s pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide. Conclusion: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide’s pharmacokinetics.

Evaluation of insulin self-dissolving micropiles by PK/PD analysis

PK/PD analysis was performed after percutaneous administration of insulin self-dissolving micropiles (SDMP) where chondroitin sulfate was used as a base. PK/PD model composed of 1-compartment open model with first-order absorption process and sigmoidal Emax model was used to simulate the time courses of both plasma insulin and glucose levels after percutaneous administration to dogs, 2.0 IU/dog. The Akaike’s information criterion (AIC) were 249.33 ± 13.00, though AIC was 259.55 ± 11.95 for the 2-compartment open model that was directly linked to sigmoidal E max model. The mean first-order absorption and elimination rate constants of insulin with SDMP were 7.59 ± 3.93 h − 1 (k 01 ) and 1.31 ± 0.66 h − 1 (k 10 ). For subcutaneous (sc) injection of insulin solution, k 01 and k 10 were 9.72 ± 5.67 h − 1 and 1.60 ± 0.45 h − 1 . PD parameter values from insulin SDMP were 148.5 ± 71.9 pg/mL for EC50 and 3.11 ± 1.41 for γ. These results suggested that insulin SDMP has almost the same PK characteristics as sc injection preparation.

Pharmacokinetic Study of Nifedipine in Healthy Adult Male Human Volunteers

Purpose: To evaluate the pharmacokinetics of nifedipine in healthy adult Pakistani subjects. Methods: Each of six fasting volunteers received 20 mg nifedipine (2 x Adalat® 10 mg capsules) orally once and then another one week later. Their blood samples were obtained at regular time intervals and analysed by HPLC. Using the non-compartmental approach, plasma levels of nifedipine were employed to compute their individual disposition kinetics, including Cmax (maximum plasma concentration), Tmax(time to reach maximum plasma concentration), MRT (mean residence time), AUC0-∞ (area under curve), AUMC0-∞ (area under first moment curve) and Ka (absorption rate constant). Results: The suggested therapeutic level of nifedipine for the treatment of hypertension (15-35 ng.mL-1) was achieved in all six volunteers within 0.25 h after dose administration, and maintained for more than 6 h. Tmax was 1.58 h and Cmax varied from 140 – 300 ng.mL-1. Mean absorption rate constant was 2.22 h-1 while mean absorption half-life was 0.43 h. The mean elimination rate constant was 0.16 h-1 while 5.7 h was recorded for terminal half-life. AUC0-¥, AUMC0-¥ and MRT were 1879.86 ng.h.mL-1, 8244.04ng.h2.mL-1 and 4.2 h, respectively. Conclusion: This study confirms the rapid absorption of nifedipine in humans. AUC was similar to thatpreviously reported for Nigerians but slightly lower than that stated in the literature for other south Asian races. Further studies on large segments of the local population using the non-compartmental model forkinetic analysis is recommended.

Population Pharmacokinetics of Mycophenolic Acid and Its 2 Glucuronidated Metabolites in Kidney Transplant Recipients

The population pharmacokinetics of mycophenolic acid (MPA) and its phenolic (MPAG) and acyl (AcMPAG) glucuronide metabolites were studied in patients taking enteric-coated mycophenolate sodium. Plasma samples (n = 232), obtained from 18 renal transplant recipients, were analyzed for MPA, MPAG, and AcMPAG using a validated high-performance liquid chromatography/ultraviolet assay. Population pharmacokinetic analysis was performed using NONMEM. The pharmacokinetics of MPA were best described by a 2-compartment model, with MPAG and AcMPAG produced from the central compartment and with enterohepatic recirculation of MPA via these 2 metabolites. Population mean estimates for MPA were apparent clearance (CL/F) of 10.6 L/h (interindividual variability [IIV] = 21.4%) and apparent volume of distribution of the central compartment (V(1)/F) of 25.9 L (IIV = 87.8%). Mean elimination rate constants of MPAG and AcMPAG were 0.323 h(-1) (IIV = 29.1%) and 0.206 h(-1) (IIV = 48.8%), respectively. The mean fraction of MPA converted to MPAG and AcMPAG, normalized by their volumes of distribution (FM(AG) and FM(AC), respectively), was also estimated. The elimination rate constant for MPAG and FM(AC) was influenced by glomerular filtration rate in patients with renal impairment. The visual predictive check, based on 100 simulated data sets each for MPA, MPAG, and AcMPAG, found that the final pharmacokinetic model adequately predicts the observed concentrations of all 3 species.

Pharmacokinetics of Ephedrine and Pseudoephedrine after Oral Administration of Kakkonto to Healthy Male Volunteers

The pharmacokinetics of serum ephedrine and pseudoephedrine as the indexed reference ingredients of Kampo Kakkonto (ge-gen-tang in Chinese) were compared after the oral administration of 2.5 g and 3.75 g of Kakkonto extract. The mean maximal serum concentrations of ephedrine and pseudoephedrine obtained after the administration at 3.75 g were 1.50- and 1.58-fold higher (p<0.05), respectively, than those obtained after the administration of 2.5 g, whereas the time required to reach the maximal concentration did not significantly differ between the two doses. The mean areas under the concentration-time curves of ephedrine and pseudoephedrine obtained after the 3.75 g of Kakkonto were 1.31- and 1.48-fold higher (p<0.05), respectively, than those obtained after the 2.5 g dose, while no significant differences were observed in the mean residence time and elimination rate constant of the terminal phase between the doses. Disposition profiles showed that the kinetic behavior of ephedrine and pseudoephedrine were largely linear at the doses examined.

Bioavailability and Pharmacokinetic Studies of Eurycomanone fromEurycoma longifolia

A validated HPLC analysis of eurycomanone (1), a bioactive quassinoid, in rat plasma following oral and intravenous administration of Eurycoma longifolia Jack extract was developed for pharmacokinetic and bioavailability studies. Relatively high plasma eurycomanone concentrations were detected after an intravenous injection of 10 mg/kg extract F2 containing 1.96 mg/kg of the quassinoid. However, it declined rapidly to zero after 8 h. Its mean elimination rate constant (k(e)), biological half-life (t(1/2)), volume of distribution (V(d)) and clearance (CL) were 0.88 +/- 0.19 h (-1), 1.00 +/- 0.26 h, 0.68 +/- 0.30 L/kg and 0.39 +/- 0.08 L/h/kg, respectively. Following oral administration of eurycomanone, its Cmax and Tmax values were detected as 0.33 +/- 0.03 microg/mL and 4.40 +/- 0.98 h, respectively. The plasma concentration of the quassinoid after oral administration was much lower than after intravenous application in spite of the oral dose being 5 times higher. The results indicate that eurycomanone is poorly bioavailable when given orally. A comparison of the AUC (0-->infinity) obtained orally to that obtained after an intravenous administration (normalized for dose differences) revealed that the absolute bioavailability of the compound was low with 10.5 %. Furthermore, the compound appeared to be well distributed in the extravascular fluids because of its relatively high V(d) value. The poor oral bioavailability was not attributed to instability problems because eurycomanone has been shown to be stable under different pH conditions. Thus, its poor oral bioavailability may be due to poor membrane permeability in view of its low P value and/or high first-pass metabolism.

A lecithin-based microemulsion of rh-insulin with aprotinin for oral administration: Investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats

The aim of this study was to develop a microemulsion formulation providing an improved efficacy of orally administered insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. The microemulsions of recombinant human (rh)-insulin and aqueous solution (200 IU/kg) were administered intragastrically by a canulla to diabetic and non-diabetic rats. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric rh-insulin solution (IS) to non-diabetic rats, the plasma glucose and insulin levels were not changed significantly. Therefore, the hypoglycemic effect caused by subcutaneous rh-insulin solution (SC), microemulsion containing rh-insulin (IME) and microemulsion containing rh-insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma glucose levels time curves (AAC), minimum glucose concentration ( C min) and time to C min ( t min) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The decrease in the plasma glucose levels continued after the 90th min. The highest AAC value was obtained when IMEA was administered to rats. The maximum plasma insulin concentration ( C max), time to reach C max ( t max), terminal half-life ( t 1/2), area under the plasma concentration–time curve (AUC), mean residence time (MRT) and elimination rate constant ( k el) values were also calculated. It was observed that t 1/2 values varied between 0.53 and 1.31 h. No significant difference could be found between the pharmacokinetic parameters of the IME and IMEA administered groups. Addition of aprotinin to the microemulsion containing rh-insulin increased bioavailability when compared to those not containing it, although the difference is not significant.

Normal plasma lactose concentrations and kinetics of intravenously infused lactose in cattle

Plasma lactose concentration and its kinetics were determined in apparently normal cattle, as a prelude to investigating its chemotherapeutic significance in bovine trypanosomiasis. It is hoped that intravenously administered lactose may be able to reduce the rate of sequestration of desialylated erythrocytes during Trypanosoma vivax infection of cattle; thus decreasing the rate of development of trypanosomal anaemia in infected animals. A range of 0·061 to 0·55 mM with a mean of 0·208 ± 0·128 mM standard deviation (SD), observed in adult cattle was significantly lower (P<0·001) than corresponding values in recently weaned calves; 0·429 to 1·496 mM (0·972 ± 0·318 mM). Semi-logarithmic plots from calves given a single dose (0·5 g lactose per kg bodyweight as a solution in normal saline, infused at the rate of 18 ml min −1) showed a biexponential pattern of regression lines. Decrease in plasma concentrations was biphasic and lactose was rapidly distributed into the extravascular space after administration. The biological half-life ( t 1 2 ) of the infused lactose ranged from 4·10 to 6·00 hours (5·01 ± 0·81 hours); its mean elimination rate constant was 0·14 ± 0·02 hour −1, mean apparent volume of distribution was 168·09 ± 56·65 ml kg −1 while its mean total clearance was 23·54 ± 8·31 ml kg −1 hours. A single dose rapidly reached a peak and gradually fell below the pre-infusion level while repeated doses did not cause accumulation of the lactose in the plasma as each infusion fell back to normal relatively rapidly.

Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock

Objectives: The objectives of this study were to determine the pharmacokinetics of milrinone lactate in pediatric patients with septic shock and to determine whether a relationship exists between steady-state plasma milrinone concentrations and changes in hemodynamic variables. Study design: This was a randomized, double-blind, placebo-controlled, interventional study. In study phase 1 patients were randomized and underwent loading and infusion with milrinone lactate (50 μg/kg, then 0.5 μg/kg/min), and invasive hemodynamic values were determined. Steady-state was determined by obtaining plasma samples at 30, 15, and 0 minutes before the end of the milrinone infusion. Study phase 2 started when milrinone was discontinued by the patient care team. Steady-state was reaffirmed and plasma samples were obtained at 0.5, 1, 2, 4, 6, and 8 hours after the end of the infusion. Results: The average plasma concentration at steady-state (Css avg) and total body clearance for phase 1 were 81.3 ± 38.6 ng/ml (mean ± SD) and 0.0106 ± 0.0053 L/kg/min, respectively ( n = 9). All but two patients underwent reloading with milrinone. In phase 2 Css avg and total body clearance were 65.8 ± 42.1 ng/ml and 0.0110 ± 0.0096 L/kg/min, respectively ( n = 11). The average time of infusion was 51 ± 21 hours. Eight patients were evaluated for phase 2 elimination. The mean elimination rate constant was 0.0091 ± 0.0061 min 1 ( n = 8). The median half-life was 1.47 hours (range, 0.62 to 10.85 hours). All patients had creatinine clearances greater than 61 ml/min/1.73 m 2. The volume of distribution at steady-state was 1.47 ± 1.03 L/kg. No correlation existed between age and the elimination rate constant or the volume of distribution at steady-state. All patients achieved at least a 20% change in cardiac index and systemic vascular resistance index while maintaining a Css avg of 35 to 160 ng/ml. No adverse effects were noted. All patients achieved primary hemodynamic end points (cardiac index and systemic vascular resistance index) during the milrinone infusion. Conclusions: Loading doses of 75 μg/kg milrinone lactate and starting infusion rates of 0.75 to 1.0 μg/kg/min for patients with normal renal function should be used; the infusion rate should then be titrated to effect. We recommend that for every increase of 0.25 μg/kg/min, a 25 μg/kg bolus dose be given. Because the median half-life is 1.47 hours, immediate hemodynamic effects may not be seen unless appropriate loading doses and infusion adjustments are made. (J Pediatr 1998;132:329-34)

A Kinetic Model for Simultaneous Fit of Clozapine and Norclozapine Concentrations in Chronic Schizophrenic Patients during Long-Term Treatment

The pharmacokinetic profiles of clozapine and its main metabolite, norclozapine, were investigated in 18 chronic schizophrenic inpatients during long-term treatment. Patients received stable daily doses (between 300 and 900mg) for at least 1 month. Plasma drug concentrations were determined by high performance liquid chromatography. The pharmacokinetic parameters were calculated from both noncompartmental and compartmental approaches with zero-order input rate using a kinetic model for simultaneous fit of clozapine and norclozapine (active metabolite) concentrations. Large interpatient variations in pharmacokinetic parameters of the two drugs were observed. Plasma clozapine concentration peaked on average at 2 hours. The mean elimination rate constants from compartments 1 (k(10)) and 2 (k(20 ), elimination rate constant of norclozapine) were 0.087 and 0.156h(-1), respectively. The rate of formation of norclozapine, k(12), averaged 1.25h(-1). The mean fraction of the administered dose converted to norclozapine was estimated to be 66%. The apparent clearance of clozapine (CL/F) averaged 44.7 L/h and the volume of distribution (V(c)/F) was 7.00 L/kg. The pharmacokinetics of clozapine after multiple doses were linear over the range of clozapine plasma concentrations of 145 to 1411 microg/L. This is the first study assessing the pharmacokinetic profile of clozapine plus norclozapine in plasma during long-term treatment. This pharmacokinetic model can be used to determine the population pharmacokinetic parameters of clozapine and norclozapine in order to optimise individual dosage regimens using a Bayesian methodology.

Determination of kinetic parameters for prothrombin complex activity during initiation of anticoagulation

Objective: A prospective determination of the kinetic parameters of prothrombin complex activity (PCA) during initiation of anticoagulation in seven adult patients (4 males and 3 females, age 62·9±5·8 years, mean±SD) receiving anticoagulant therapy with warfarin.Method: All excluding one patient received a fixed daily dose of 5 mg warfarin over an initial 3 days. Three successive daily doses of warfarin were recorded, together with the corresponding PCA. The kinetic parameters for elimination of PCA during the initiation of anticoagulation were estimated from the log PCA–time plot with a 1-compartment model.Results: The mean elimination rate constant (kp) of PCA was 0·377 day−1 (range 0·242–0·588 day−1) during initiation of anticoagulation. The coefficient of variation in kp was about 28%, indicating the considerable inter-individual differences in PCA response to warfarin. The mean plasma half-life of PCA was 1·96 days. There were no significant relationships (by simple regression analysis) between kp and cumulative warfarin doses per kg of body weight or age during initiation of anticoagulation.Conclusion: The results suggest that for a 50% reduction of PCA, one would need about 2 days after initiation of anticoagulation.

Determination of kinetic parameters for prothrombin complex activity during initiation of anticoagulation

A prospective determination of the kinetic parameters of prothrombin complex activity (PCA) during initiation of anticoagulation in seven adult patients (4 males and 3 females, age 62.9 +/- 5.8 years, mean SD) receiving anticoagulant therapy with warfarin. All excluding one patient received a fixed daily dose of 5mg warfarin over an initial 3 days. Three successive daily doses of warfarin were recorded, together with the corresponding PCA. The kinetic parameters for elimination of PCA during the initiation of anticoagulation were estimated from the log PCA-time plot with a 1-compartment model. The mean elimination rate constant (kp) of PCA was 0.377 day(-1) (range 0.242-0-588 day (-1)) during initiation of anticoagulation. The coefficient of variation in kp was about 28%, indicating the considerable inter-individual differences in PCA response to warfarin. The mean plasma half-life of PCA was 1.96 days. There were no significant relationships (by simple regression analysis) between kp and cumulative warfarin doses per kg of body weight or age during initiation of anticoagulation. The results suggest that for a 50% reduction of PCA, one would need about 2 days after initiation of anticoagulation.

Repeated assessment of methylprednisolone pharmacokinetics during chronic immunosuppression in renal transplant recipients.

To compare the pharmacokinetics of methylprednisolone in renal transplant recipients on 2 occasions separated by at least 1 month during chronic immunosuppression. A prospective unblinded trial. Ten renal transplant recipients (aged 25-62 years) evaluated in a public university-affiliated hospital clinic. All patients received their chronic oral dose of methylprednisolone as a 10-20-minute intravenous infusion during the 2 study periods. Serum methylprednisolone concentrations were determined by HPLC and were used to generate the pharmacokinetic parameters of the drug. During study 1, which ranged from 1.2 to 24 months posttransplant, the mean +/- SD methylprednisolone dose was 13.2 +/- 6.4 mg. In study 2 (2.5-38.5 mo posttransplant), the mean dose was 10.6 +/- 3 mg. During both study periods, methylprednisolone concentrations exhibited a monoexponential decline. Considerable variability in methylprednisolone clearance was observed between periods in certain patients. Four of the 10 patients demonstrated a reduction in clearance from study 1 to study 2, which ranged from a 28% to a 53% decrease. Two patients exhibited an increase in clearance of 40% and 49%. The mean +/- SD total body clearance in study 1 was 363 +/- 330 mL/min/kg, whereas the mean volume of distribution was 1.18 +/- 0.53 L/kg. The mean elimination rate constant was 0.29 +/- 0.14 h-1, with a mean serum half-life of 2.87 +/- 1.15 h during the first phase. In study 2, the mean methylprednisolone clearance was 261 +/- 150 mL/min/kg (p > 0.05) and the mean volume of distribution was 0.89 +/- 0.31 L/kg (p > 0.05). The mean serum half-life of methylprednisolone was 2.91 +/- 0.60 h (p > 0.05), with the mean elimination rate constant of 0.25 +/- 0.06 h-1 (p > 0.05). These data demonstrate that intrapatient variability in methylprednisolone clearance exists among certain renal allograft recipients. As a result of the observed variability, patients who are continued on the same dose of methylprednisolone during the posttransplant period of chronic immunosuppression will be subjected to a changing pattern of exogenous glucocorticoid exposure. The impact of these changing patterns requires further prospective evaluation.

Vancomycin pharmacokinetics in spinal cord injured patients: a comparison with age-matched, able-bodied controls.

To compare the pharmacokinetics of vancomycin in chronic spinal cord injured patients and hospitalized, age-matched, able-bodied controls, we evaluated 14 spinal cord injured patients and 14 controls. Pharmacokinetic parameters of total body clearance (CL), distribution volume (V), elimination rate constant (k) and elimination half-life (t1/2) were calculated from two steady-state vancomycin serum concentrations by the method of Sawchuk and Zaske. Demographic data such as age, ideal body weight (IBW), total body weight (TBW) and serum creatinine at start of therapy (SCr), pharmacokinetic parameters and predicted dosages to achieve specific peak (30 mcg/ml) and through concentrations (5-10 mcg/ml) were calculated for both groups. Statistical comparisons were made using a two sample, Student's t-test. Demographic data between groups differed only in mean serum creatinine (p = 0.04). There were no statistically significant differences in mean pharmacokinetic parameters of CL and V or mean predicted dosages. Mean elimination rate constant was significantly smaller and mean elimination half-life was significantly longer in spinal cord injured patients (p = 0.02 and p = 0.04, respectively). The longer dosing interval predicted in spinal cord injured patients trended toward statistical significance (p = 0.10). We conclude that with chronic spinal cord injury, 1) the elimination half-life of vancomycin is increased and these patients may require longer dosing intervals and 2) distribution volume and predicted vancomycin doses are unaltered compared with controls.

Population Pharmacokinetics of Vamicamide in Healthy Volunteers.

The pharmacokinetic data of vamicamide, a new anticholinergic drug, collected from healthy male subjects were analysed to estimate population pharmacokinetic parameters. A total of 48 subjects participated in three single-dose studies and three multiple-dose studies. In the single-dose studies, the subjects were given vamicamide tablets or capsules in doses of 0.7 to 48 mg, and in the multiple-dose studies, doses of 6, 12 or 36 mg two or three times a day for six days. These six studies were conducted independently in two different facilities using the two different dosage forms. Subjects were given the drug after a meal or in a fasting state depending on each study. 931 serum vamicamide concentration data and 143 urinary vamicamide excretion data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis. The pharmacokinetic model used was a one-compartment model with first-order absorption. A linear or nonlinear regression model was used to evaluate the effects of bodyweight, age, dosage form or food intake on the pharmacokinetic parameters of vamicamide. The mean elimination rate constant (Ke), apparent volume of distribution (Vd/F) and urinary recovery were estimated to be 0.137 hr-1, 2.24 L/kg and 91.6%, respectively. Vd/F varied linearly with bodyweight. Food intake significantly affected absorption rate constant (Ka) and lag time of absorption (to) but not Vd/F. Ka increased from 1.75 hr-1 in a fasting state to 2.63 hr-1 after a meal, and t0 increased from 0.178 hr to 0.347 hr. These increases, however, did not cause any clinically significant difference in maximum serum concentrations, suggesting that the bioavailability of vamicamide appears to be little affected by food intake. Dosage form and subject age, in the range of 22 to 46 years, had no signifficant effect on the pharmacokinetics of vamicamide. The estimates of in terindividual variabilities were 71.3% in Ka, 12.8% in Ke and 11.7% in Vd/F as a coefficient of variation. The residual variabilities in the serum concentrations and in the urinary excretion were 16.5% and 12.0%, respectively.

Pharmacokinetics of metronidazole after rectal administration in horses

Summary Five healthy adult mares and 1 gelding were given a single dose (15 mg/kg of body weight) of metronidazole per rectum. After manual evacuation of feces from the rectum, a suspension of crushed tablets and water (40 ml) was administered via a 28-F catheter advanced 30 cm into the rectum. Blood samples were obtained by jugular venipuncture, and metronidazole concentration was measured serially for the 14 hours after drug administration. Mean serum concentration of metronidazole peaked at 4.5 μg/ml, 0.83 hour after administration, and decreased to 0.38 μg/ml, 14 hours after administration. Mean elimination rate constant was 0.23/h, and the harmonic mean elimination half-life was 3.04 hours. Further study is necessary to determine a therapeutic dose regimen for metronidazole administered per rectum.

Steady-state pharmacokinetics of dopamine in adult patients

To study the pharmacokinetics of dopamine in hemodynamically stable adult patients. Prospective clinical study. University hospital intensive care unit. Fourteen patients (aged 43 to 73 yrs) recovering from esophageal surgery. Dopamine was infused and blood samples were collected. Plasma dopamine concentrations were measured at steady state and subsequently at the end of the dopamine infusion using high-performance liquid chromatography. Clearances, volume of distribution, mean residence times, half-lives, and elimination and distribution rate constants were derived. The clearances were independent of the infusion rate at 1, 3, and 6 micrograms/kg/min, and ranged between 0.050 and 0.056 L/min/kg. A two-compartment open model was fitted to the postinfusion plasma concentration data obtained at 3 and 6 micrograms/kg/min. On average, the steady-state volume of distribution and the apparent terminal elimination half-life increased with the dose: 0.78 to 1.58 L/kg, respectively, and 22.1 to 37.9 mins, respectively, for the rates of 3 and 6 micrograms/kg/min. The rate constant associated with the uptake of dopamine into the peripheral compartment (K12) was on average four to five times higher than the rate constant associated with the reverse process (K21). The redistribution of dopamine into the central compartment could be the main factor involved in the apparent terminal elimination of dopamine from plasma. Due to the relative rates of distribution and elimination, the attainment of a steady-state plasma concentration of dopamine should only depend on the terminal half-life. These results, which remain to be validated in a greater number of patients, indicate that the attainment of 90% of the plateau (i.e., in 3.3 half-lives) would require 70 to 125 mins, depending on the infusion rate.

Urinary mercury excretion in chloralkali workers after the cessation of exposure.

Seventeen former chloralkali workers were followed through the regular determination of urinary mercury for nearly two years after the cessation of exposure to mercury vapor in a study of the time course of urinary mercury elimination. Their duration of exposure ranged from 3 d to 35.5 years. A one-compartment model for urinary mercury elimination was applied. The urinary mercury concentration declined at a rate indicating a half-time of 91 d. When corrected for an individual base-line level of urinary mercury resulting from sources of mercury intake not related to work, the half-time was 72.4 [95% confidence interval (95% CI) 63.2-81.7] d, with a mean elimination rate constant of 0.011 (95% CI 0.008-0.013).d-1. The day-to-day variability of the urinary mercury concentration averaged 22%, expressed as the coefficient of variation between urine samples delivered on three consecutive days.