Three-compartment Mammillary Model Research Articles

Population Pharmacokinetics and Absolute Oral Bioavailability of Lasalocid after Single Intravenous and Intracrop Administration in Laying Hens.

Lasalocid sodium is a polyether carboxylic ionophore agent authorized by the EU for use as a coccidiostat in broilers, turkeys, and pullets up to 16 weeks of age, except for laying hens. However, laying hens are the most common nontarget species exposed to lasalocid sodium, mainly due to cross-contamination from feed mills. This exposure may result in potential drug residue deposition in eggs, which could potentially expose consumers to the drug. The breeds commonly used for commercial egg production in Poland are Isa Brown and Green-legged Partridge hens, which have been found to significantly differ in egg-laying performance. This variability may also affect the pharmacokinetics of lasalocid. Data on lasalocid plasma pharmacokinetics in laying hens are lacking. In this study, we aimed to determine typical population pharmacokinetic parameters, absolute oral bioavailability, and how breed may influence the pharmacokinetics of lasalocid. Twenty-layer hens of the two breeds were used in this study. Lasalocid was administered orally at a single dose of either 1 mg or 5 mg/kg body weight or intravenously at a dose of 1 mg/kg body weight, in a crossover design with a three-week washout period between study periods. Blood samples were collected for 72 h, and lasalocid concentrations were measured using high-performance liquid chromatography with fluorescence detection. A population pharmacokinetic analysis was conducted using nonlinear mixed effects modeling. Standard numerical and graphical criteria were used to select the best model, and a stepwise covariate modeling approach was used to determine any influencing factors. The best model was a three-compartment mammillary model with first-order absorption, transit compartments, and linear elimination. The estimated absolute oral bioavailability was low (36%). It was found that breed significantly influenced not only absorption but also the elimination of lasalocid. This study revealed that lasalocid absorption and elimination varied between the two breeds. This variability in pharmacokinetics may result in breed-related differences in drug residue accumulation in eggs, and ultimately, the risk associated with consumer exposure to drug residues may also vary.

Population pharmacokinetic and pharmacodynamic model of propofol externally validated in Korean elderly subjects.

The Eleveld propofol pharmacokinetic (PK) model, which was developed based on a broad range of populations, showed greater bias (- 27%) in elderly subjects in a previous validation study conducted by Vellinga and colleagues. We aimed to develop and externally validate a new PK-pharmacodynamic (PK-PD) model of propofol for elderly subjects. A population PK-PD model was constructed using propofol plasma concentrations and bispectral index (BIS) values that were obtained from 31 subjects aged 65years older in previously published phase I studies. The predictive performance of the newly-developed PK-PD model (Choi model) was assessed in a separate Korean elderly population and compared with that of the Eleveld model. A three-compartment mammillary model using an allometric expression and a sigmoid Emax model well-described the time courses of propofol concentrations and BIS values. The V1, V2, V3, Cl, Q1, Q2, E0, Emax, Ce50, γ, and ke0 of a 60-kg subject were 8.36, 58.0, 650 L, 1.26, 0.917, 0.669 L/min, 92.1, 18.7, 2.21μg/mL, 2.89, and 0.138 /min, respectively. In the Choi model and Eleveld model, pooled biases (95% CI) of the propofol concentration were 7.78 (3.09-12.49) and 16.70 (9.46-23.93) and pooled inaccuracies were 22.84 (18.87-26.81) and 24.85 (18.07-31.63), respectively. The Choi PK model was less biased than the Eleveld PK model in Korean elderly subjects (age range: 65.0-79.0yr; weight range: 45.0-75.3kg). Our results suggest that the Choi PK model, particularly, is applicable to target-controlled infusion in non-obese Korean elderly subjects.

The expected advantage of administering prophylactic antibiotics using target‐ concentration controlled infusion: Development of a new pharmacokinetic model of cefazolin

The aim of this study was to explore the utility of target-concentration controlled infusion (TCI) as a prophylactic antibiotic administration method based on the results of a population pharmacokinetic model of cefazolin. In patients undergoing elective gastric surgery, 2g of cefazolin was dissolved in 50 mL of saline and administered for 10min prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefazolin. Population pharmacokinetic analysis was performed using non-linear mixed-effects modelling. To evaluate the effectiveness of the TCI method, stochastic simulation was performed based on the model construction results. In total, 360 total and 360 free plasma concentration measurements from 40 patients were used to characterise the pharmacokinetics of cefazolin. The changes in the total concentration of cefazolin over time were well-explained by the three-compartment mammillary model. Fat-free mass and estimated glomerular filtration rate were significant covariates. The probability of target attainment (PTA) to reach the target 100% fraction of time that the free plasma concentration of cefazolin was maintained above its minimal inhibitory concentration (fT > MIC) at MIC of 4mg/L was also notably higher in the TCI method (90.7%) than in the standard method (17.0%). When cefazolin is administered by the TCI method, patient-tailored antibiotic dosing may be possible. The potential benefits of administering prophylactic antibiotics by the TCI method were observed. Further research is warranted to confirm the effectiveness of the TCI method.

Development of a new pharmacokinetic model for target-concentration controlled infusion of vancomycin in critically ill patients.

The aim of this prospective study was to construct a new pharmacokinetic model of vancomycin for target-concentration controlled infusion (TCI). As the first loading dose, 25mg/kg of vancomycin was administered during 60-90min. Arterial blood samples were obtained at pre-set intervals to measure the serum concentrations of vancomycin. Population pharmacokinetic analysis was performed using the NONMEM software (ICON Development Solutions). In total, 197 serum concentration measurements from 22 patients were used to characterise the pharmacokinetics of vancomycin. A three-compartment mammillary model best described the pharmacokinetics of vancomycin in critically ill patients. The ideal body weight was a significant covariate for the central and slow peripheral volume of distribution. The weight and age converted to categorical variables at a cut-off of 65years were a significant covariate for the clearance. Based on the results of stochastic simulation, the TCI method maintained the therapeutic concentration range for the longest duration. In addition, assuming that vancomycin was administered by the TCI method for 7days, the dose was reduced by about 15% compared with the standard administration methods. The daily area under the curve values were maintained between 500mg·h/L and 600mg·h/L. TCI has the potential to become a new infusion method for patient-tailored dosing in critically ill patients. To administer vancomycin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.

Development of a new pharmacokinetic model for target-concentration controlled infusion of cefoxitin as a prophylactic antibiotic in colorectal surgical patients.

There are several limitations to the existing method of administering cefoxitin as a prophylactic antibiotic, and the limitations may be overcome by applying the target-concentration controlled infusion (TCI) method. Population pharmacokinetic parameters are required to administer cefoxitin by the TCI method. The aim of this study was to construct a new pharmacokinetic model of cefoxitin for the TCI method in colorectal surgical patients. In patients undergoing colorectal surgery, 2 g of cefoxitin was dissolved in 50 mL of saline and administered for 10 minutes prior to skin incision. Arterial blood samples were obtained at preset intervals to measure the total and free plasma concentrations of cefoxitin. Population pharmacokinetic analysis was performed using NONMEM software (ICON Development Solutions, Dublin, Ireland). Additionally, stochastic simulation was used to indirectly evaluate the effectiveness of the two administration methods (standard method vs TCI). In total, 297 plasma concentration measurements from 31 patients were used to characterize the pharmacokinetics of cefoxitin. A three-compartment mammillary model described the pharmacokinetics of cefoxitin. Body weight and creatinine clearance were significant covariates for clearance. The stochastic simulation showed that when compared with the standard method, the TCI method has a significantly higher fraction of time that the free concentration of cefoxitin is maintained above the minimum inhibitory concentration (P < .001). TCI has the potential to become a new infusion method for patient-tailored dosing in surgical patients. To administer cefoxitin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.

An allometric pharmacokinetic model and minimum effective analgesic concentration of fentanyl in patients undergoing major abdominal surgery

BackgroundWe aimed to characterise the population pharmacokinetics of fentanyl in adults and to determine the minimum effective concentration (MEC) and minimum effective analgesic concentration (MEAC) of i.v. fentanyl in patients after major abdominal open surgery. MethodsIn the pharmacokinetic study, subjects received an intravenous bolus of fentanyl 100 μg during operation, and arterial blood was sampled at pre-set intervals. In addition, data from previously published fentanyl pharmacokinetic studies were incorporated to build a pharmacokinetic model. In the MEAC study, subjects were asked to rate their pain every 10 min using a VAS (0=no pain, 10=most severe pain) in the PACU. The first blood sample was obtained when wound pain was rated as ≥3 at rest or ≥5 during compression. Then, fentanyl 50 μg was administered every 10 min until the pain intensity had decreased to <3 at rest and <5 during compression, at which point the second blood was sampled and the first MEAC of fentanyl was measured. The same procedure was repeated to obtain a third sample (MEC) and a fourth sample (second MEAC). ResultsIn the population pharmacokinetic study (n=95), the plasma concentration of fentanyl over time was well-described by the three-compartment mammillary model using an allometric expression. The V1, V2, V3, Cl, Q1, and Q2 of a 70 kg subject were 10.1, 26.5, 206 L, 0.704, 2.38, and 1.49 L min−1, respectively. In the MEAC study (n=30), the median (inter-quartile range) MEC and MEAC were 0.72 (0.58–1.05) ng ml−1, and 0.99 (0.76–1.28) ng ml−1, respectively. ConclusionThese results provide a scientific basis for the use of fentanyl for acute postoperative pain management in surgical patients. Clinical trial registrationKCT0003273 (http://cris.nih.go.kr).

Population pharmacokinetic analysis of propofol in underweight patients under general anaesthesia

BackgroundThe modified Marsh and Schnider pharmacokinetic models for propofol consistently produce negatively and positively biased predictions in underweight patients, respectively. We aimed to develop a new pharmacokinetic model of propofol in underweight patients. MethodsTwenty underweight (BMI<18.5 kg m−2) patients aged 20–68 yr were given an i.v. bolus of propofol (2 mg kg−1) for induction of anaesthesia. Anaesthesia was maintained with a zero-order infusion (8 mg kg−1 h−1) of propofol and target-controlled infusion of remifentanil. Arterial blood was sampled at preset intervals. A population pharmacokinetic analysis was performed using non-linear mixed effects modelling. The time to peak effect (tpeak, maximally reduced bispectral index) was measured in 28 additional underweight patients receiving propofol 2 mg kg−1. ResultsIn total, 455 plasma concentration measurements from the 20 patients were used to characterise the pharmacokinetics of propofol. A three-compartment mammillary model well described the propofol concentration time course. BMI and lean body mass (LBM) calculated using the Janmahasatian formula were significant covariates for the rapid peripheral volume of distribution and for the clearance of the final pharmacokinetic model of propofol, respectively. The parameter estimates were as follows: V1(L)=2.02, V2(L)=12.9(BMI/18.5), V3(L)=139, Cl (L⋅min−1)=1.66(LBM/40), Q1 (L⋅min−1)=1.44, Q2 (L⋅min−1)=0.87+0.0189×(LBM−40). The median tpeak of propofol was 1.32 min (n=48). ConclusionsA three-compartment mammillary model can be used to administer propofol via target effect-site concentration-controlled infusion of propofol in underweight patients. Clinical trial registrationKCT0001760.

Population pharmacokinetics of ramosetron.

Ramosetron is a selective serotonergic 5-hydroxy-tryptamine receptor 3 antagonist that is used to prevent and treat postoperative nausea and vomiting. This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19-80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM(®)). The pharmacokinetics of ramosetron was best described by a three-compartment mammillary model with first-order elimination. Based on allometric principles, body weight was incorporated in the base model, along with fixed allometric exponents. The typical value of clearance was 0.19 L/h in a 60-kg subject, and it decreased approximately 3% for every year of age, starting at age of 57. The bootstrap method and visual predictive check showed that the final pharmacokinetic model was appropriate. A population pharmacokinetic model of ramosetron was constructed in adult surgical patients, providing a foundation for further defining the relationship between ramosetron dose and postoperative nausea and vomiting.

Association between zinc pool sizes and iron stores in premenopausal women without anaemia

The simultaneous occurrence of Zn and Fe deficiencies in man has been known since the discovery of human Zn deficiency. However, it is not established that low Fe stores per se or Fe-deficiency anaemia infer low Zn status. Therefore our objective was to identify relationships between Zn and Fe status in premenopausal women without anaemia. We also examined the contribution of food frequencies and blood loss to Zn and Fe status. The subjects were thirty-three apparently healthy premenopausal women without anaemia, who were not taking dietary supplements containing Zn or Fe or oral contraceptives. Main outcomes were Zn kinetic parameters based on the three-compartment mammillary model and serum ferritin (SF) concentration; contributing factors were the frequency of consumption of specific foods and menorrhagia. Lower SF was significantly associated with smaller sizes of Zn pools. The breakpoint in the relationship between SF and the lesser peripheral Zn pool was found to be 21.0 microg SF/l. SF also correlated positively with frequency of beef consumption and negatively with bleeding through menstrual pads (BTMP). Similar to SF, the Zn pool sizes correlated positively with frequency of beef consumption, and negatively with BTMP. In summary, Zn pool sizes and Fe stores were highly correlated in premenopausal women. SF concentrations < 20 microg/l suggest an increased likelihood of low Zn status.

Association between plasma zinc concentration and zinc kinetic parameters in premenopausal women.

The objective of this study was to measure relationships between plasma zinc (Zn) concentrations and Zn kinetic parameters and to measure relationships of Zn status with taste acuity, food frequency, and hair Zn in humans. The subjects were 33 premenopausal women not taking oral contraceptives and dietary supplements containing iron and Zn. Main outcomes were plasma Zn concentrations, Zn kinetic parameters based on the three-compartment mammillary model using 67Zn as a tracer, electrical taste detection thresholds, and food frequencies. Lower plasma Zn was significantly (P < 0.01) associated with smaller sizes of the central and the lesser peripheral Zn pools, faster disappearance of tracer from plasma, and higher transfer rate constants from the lesser peripheral pool to the central pool and from the central pool to the greater peripheral pool. The break points in the plasma Zn-Zn kinetics relationship were found between 9.94 and 11.5 micromol/l plasma Zn. Smaller size of the lesser peripheral pool was associated with lower frequency of beef consumption and higher frequency of bran breakfast cereal consumption. Hypozincemic women with plasma Zn <10.7 micromol/l or 700 ng/ml had decreased thresholds of electrical stimulation for gustatory nerves. Our results based on Zn kinetics support the conventional cutoff value of plasma Zn (10.7 micromol/l or 700 ng/ml) between normal and low Zn status.

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.

The pharmacokinetics of lignocaine in humans during a computer-controlled infusion

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5μg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V 1 = 7.44, V 2 =11.5 and V 3 = 97.71; Cl 1 = 0.585, Cl 2 = 2.23 and Cl 3 =1.64 Umin. Similarly calculated parameters using NONMEM were V 1 = 6.99, V 2 =12.2 and V 3 =1341; Cl 1 = 0.703, Cl 2 =1.24 and Cl 3 =1.49 Umin. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.

The pharmacokinetics of 8‐methoxypsoralen following i.v. administration in humans [see comments

1. 8-methoxypsoralen (8-MOP) is a naturally occurring photoreactive substance which, in the presence of u.v. light, forms covalent adducts with pyrimidine bases in nucleic acids. For many years, 8-MOP has been used in PUVA therapy for treatment of psoriasis. Recently, the drug has been found to inactivate effectively bacteria spiked into platelet concentrates. The purpose of this study was to determine the pharmacokinetics and safety of 8-MOP administered intravenously in the bactericidal dosage range. 2. Eighteen volunteers were divided into three treatment groups to receive, respectively, 5, 10, and 15 mg 8-MOP infused over 60 min. Frequent arterial samples were gathered, and the blood and plasma were assayed for 8-MOP concentration. The pharmacokinetic parameters were determined by moment and compartmental population analysis, the latter performed with the program NONMEM. Haemodynamics, ventilatory pattern, and subjective effects were recorded throughout the study. 3. The intravenously administered 8-MOP was well tolerated in all individuals, and no acute toxicity was observed. 4. The pharmacokinetics of 8-MOP were best described by a three-compartment mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters for the plasma concentrations were: V1 = 0.045 1 kg-1, V2 = 0.57 1 kg-1, V3 = 0.15 1 kg-1, CL1 (systemic) = 0.010 1 kg-1 min-1, CL2 = 0.0067 1 kg-1 min-1, CL3 = 0.012 1 kg-1 min-1. The mean pharmacokinetic parameters for the blood concentrations were: V1 = 0.061 1 kg-1, V2 = 1.15 1 kg-1, V3 = 0.21 1 kg-1, CL1 (systemic) = 0.015 1 kg-1 min-1, CL2 = 0.011 1 kg-1 min-1 and CL3 = 0.015 1 kg-1 min-1. 5. The plasma pharmacokinetic model described the observations with a median absolute error of 17%, and the blood pharmacokinetic model described the observations with a median absolute error of 18%. Analysis of the relative concentration of 8-MOP between plasma and red blood cells suggested concentration-dependent partitioning. 6. The addition of 7.5 mg 8-MOP to 300 ml platelet concentrate would produce bactericidal concentrations of 25 micrograms ml-1. Simulations based upon our data show that intravenous administration of 7.5 mg over 60 min would result in systemic concentrations of 8-MOP similar to those observed with conventional PUVA therapy. We conclude that the extensive safety history established in PUVA therapy will be applicable to this new application of 8-MOP.

PHARMACOKINETIC INTERACTION OF PROPOFOL AND FENTANYL: SINGLE BOLUS INJECTION STUDY

The effect of pretreatment with fentanyl on the pharmacokinetics of a single bolus of propofol was studied in 17 female patients (mean age 35 yr), ASA grade I. Eight patients received fentanyl 1.5 micrograms kg-1 5 min before induction of anaesthesia. In all patients anaesthesia was induced with propofol 2.5 mg kg-1 and maintained with halothane and nitrous oxide in oxygen. Pretreatment with fentanyl resulted in prolonged apnoea in all eight patients compared with three of nine patients in the control group. The pharmacokinetic values for propofol were described by a three-compartment mammillary model with rapid distribution phases (T1/2 alpha mean (SEM) 3.1 (2.0) min and T1/2 beta 44 (9.1) min) and a slower final phase of T1/2 gamma 520 (96) min. The clearance of propofol was rapid (mean 1.6 (0.24) litre min-1). Propofol was distributed initially into a relatively large central compartment (mean 23.7 (6.6) litre) and was extensively redistributed (mean Vss 593 (157) litre). There was no difference in the pharmacokinetic profile of propofol between the two groups.

Influence of increased metabolic rate on [13C]bicarbonate washout kinetics

The effect of changes in metabolic rate on the dynamics of CO2 exchange among its various compartments in the human body is not well understood. We examined CO2 dynamics in six healthy male subjects using an intravenous bolus of [13C]bicarbonate. Subjects were studied while resting, during light exercise [50% of the lactate threshold (LT), 3-4 times resting O2 uptake (VO2)], and during moderate exercise (95% of the LT, 6 times resting VO2). The sum of three exponential terms well described the washout of 13CO2 in exhaled breath both at rest and during each exercise level despite substantial increases in metabolic rate accompanying the exercise studies. Average recovery of 13C label rose from 67% during rest to 80% during light and moderate exercise (P less than 0.01). The estimate of CO2 elimination (VCO2) calculated from the washout parameters and corrected for recovery was in very good agreement with the VCO2 directly measured simultaneously breath by breath (r = 0.993, SE for VCO2 = 0.079 l/min). By use of a three-compartment mammillary model, the quantity of CO2 in the central pool (Q1) doubled from rest to light exercise (233 +/- 60 to 479 +/- 76 mmol, P less than 0.01) but did not change further with moderate exercise (458 +/- 74 mmol). Rate constants for exchange between pools and for irreversible loss from the system tended to increase with metabolic rate, but there was large variation in the responses. We conclude that the compartmental dynamics of CO2 transport and storage are very sensitive to changes in metabolic rate induced by exercise.

Compartment analysis of metabolism of chromium(III) in rats of various ages.

The metabolism of chromium(III) was studied in groups of female Wistar rats of various ages (35, 60, and 120 days) after a single intravenous injection of 51CrCl3 in trace amounts. In all the animals, the plasma disappearance curve could be adequately described by a sum of three exponential terms between 0 and 265 h postinjection. A three-compartment mammillary model is proposed that permits the description of Cr(III) metabolism in quantitative terms. The model defines compartment volumes, clearances by exchange, and clearances by excretion. The total excretory clearance is the sum of three components: urinary clearance (fu), fecal clearance (fd), and a residual clearance (fs), corresponding to an apparently irreversible deposition of chromium into long term body reservoirs. The parameters of the model are reported for each age group; when their values are expressed per 100 g of body wt, all the components of the excretory clearance decrease with age. In all cases elimination takes place primarily via the urine and fs accounts for 31-41% of the total excretory clearance. Consistent with the model, 51Cr was found to accumulate with time in several organs such as bone, kidney, spleen, and liver after a single intravenous injection of 51CrCl3.