Time Course Of Blood Concentration Research Articles

Clearance Concepts: Fundamentals and Application to Pharmacokinetic Behavior of Drugs.

Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. In this communication, the fundamentals of the two most widely used models of hepatic metabolism, namely the well-stirred (venous equilibrium) and parallel-tube (sinusoidal perfusion) models, are reviewed. Additionally, the assumptions inherent to these models and the differences between them in terms of their predictive behavior are discussed. The effects of changes in the physiologic determinants of clearance on the blood concentration-time profiles of drugs with low and high extraction ratio are also presented using numerical examples. Lastly, interesting and unusual examples from the literature are provided where these concepts have been applied beyond their widely known applications. These examples include estimation of the oral bioavailability of drugs in the absence of otherwise needed intravenous data, differentiation between the role of liver and gut in the first-pass loss of drugs, and distinction between the incomplete absorption and first-pass metabolism in the gastrointestinal tract after the oral administration of drugs. It is concluded that the clearance concepts are a powerful tool in explaining the pharmacokinetics of drugs and predicting the changes in their blood concentration-time courses when the underlying physiologic parameters are altered due to age, disease states, or drug interactions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Development of multi-route physiologically-based pharmacokinetic models for ethanol in the adult, pregnant, and neonatal rat

Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the USA, and higher EtOH concentrations are being considered (15–85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK models were developed to describe life-stage differences in the kinetics of EtOH alone in adult, pregnant, and neonatal rats for inhalation, oral, and intravenous routes of exposure, using data available in the open literature. Whereas ample data exist from gavage and intravenous routes of exposure, kinetic data from inhalation exposures are limited, particularly at concentrations producing blood and target tissue concentrations associated with developmental neurotoxicity. Compared to available data, the three models reported in this paper accurately predicted the kinetics of EtOH, including the absorption, peak concentration, and clearance across multiple datasets. In general, model predictions for adult and pregnant animals matched inhalation and intravenous datasets better than gavage data. The adult model was initially better able to predict the time-course of blood concentrations than was the neonatal model. However, after accounting for age-related changes in gastric uptake using the calibrated neonate model, simulations consistently reproduced the early kinetic behavior in blood. This work provides comprehensive multi-route life-stage models of EtOH pharmacokinetics and represents a first step in development of models for use with gasoline-EtOH blends, with additional potential applicability in investigation of the pharmacokinetics of EtOH abuse, addiction, and toxicity.

Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships

Introduction. Chloroquine causes rare but life-threatening toxicity. The prognostic value of plasma chloroquine concentrations in acute poisonings remains poorly investigated. We investigated the hypothesis that blood chloroquine concentrations better predicted chloroquine poisoning severity than plasma concentrations. Methods. A prospective study of consecutive chloroquine poisonings admitted to an intensive care unit from 2003 to 2007 was performed with simultaneous measurements of blood and plasma chloroquine (chloroquine and desethylchloroquine) concentrations. A population pharmacokinetic–pharmacodynamic model described epinephrine infusion rate, our surrogate marker of cardiovascular toxicity, as function of blood or plasma chloroquine concentrations. Results. Forty-four patients [29F/15M, 33 years (25–41), median (25–75th percentile), 34% with cardiac arrest] were included. Management included mechanical ventilation (80%), 8.4% sodium bicarbonate (66%), epinephrine [73%, maximal rate: 2.8 mg/h (0.8–5.0)], and extracorporeal life support (16%). Seven patients died. Blood [6.7 mg/L (4.0–13.0)] and plasma [1.5 mg/L (1.2–2.9)] chloroquine concentrations were weakly, although significantly correlated (r = 0.66, p < 0.0001, Spearman test). Admission chloroquine concentrations correlated with the reported ingested dose (r = 0.70 for blood vs. 0.48 for plasma), QRS duration (r = 0.82 vs. 0.64), lactate concentrations (r = 0.63 vs. 0.47), and epinephrine infusion rates (r = 0.70 vs. 0.62). Chloroquine concentrations differed significantly between patients with and without cardiac arrest (p = 0.0002 for blood vs. 0.02 for plasma). A one-compartment pharmacokinetic (PK) model adequately described blood chloroquine concentrations. An effect compartment linked to the blood compartment adequately described plasma chloroquine concentrations. Using a sigmoidal Emax pharmacodynamic (PD) model, epinephrine infusion rate was better predicted with blood than plasma concentrations (p < 0.01), suggesting that time-course of blood concentrations is a better prognostic value than plasma concentrations. Conclusion. Immediate and serial measurements of blood chloroquine concentrations are better than plasma for predicting cardiovascular severity of chloroquine poisonings.

Lung Deposition of a Liposomal Cyclosporine A Inhalation Solution in Patients after Lung Transplantation

Bronchiolitis obliterans is the most important long-term sequelae of lung transplantation limiting survival. Optimized immunosuppression, including inhalation of cyclosporine A (CsA), may be a promising approach to overcome this problem. In this study a liposomal CsA solution was characterized in vitro, doses of 10 and 20 mg were inhaled with the PARI eFlow inhaler by 12 stable lung transplant recipients, and lung deposition was evaluated by gamma scintigraphy. Inhalation of CsA leads to lung deposition of 40 +/- 6% (10 mg) and 33 +/- 7% (20 mg), respectively. This deposition resulted in a peripheral lung dose of 2.0 +/- 0.4 mg (10 mg) and 3.4 +/- 0.8 mg (20 mg), respectively. Extrathoracic deposition was 16 +/- 6% (10 mg) and 14 +/- 4% (20 mg), respectively, and the total deposition was calculated with 56% (10 mg) and 46% (20 mg). Lung deposition and peripheral lung deposition increased significantly with treatment time. The maximum CsA blood concentration and the area under the time course of blood concentration correlated with peripheral lung deposition. There were no statistically significant differences between patients with single- and double-lung transplantation. Inhalation of the study medication was well tolerated, and led to only minor but statistically significant changes in lung function parameters (FEV(1): -0.07 L; FVC: -0.09 L; sRaw: +0.35 kPa s.). The new liposomal CsA PARI formulation can be deposited to the peripheral lung using the PARI eFlow nebulizer. The treatment was well tolerated, and no drug-related side effects were observed. Once or twice daily dosing of 10 mg CsA A PARI would result in a sufficient peripheral lung deposition of approximately 14 and 28 mg/week, respectively.

Curvature‐adjusted optimal design of sampling times for the inference of pharmacokinetic compartment models

In pharmacokinetics, compartment models are often used to describe the time course of blood concentration after the administration of a drug. In this article, we propose an optimal design criterion for precise estimation of parameters included in the compartment model and illustrate the non-sequential design of sampling times of blood drug concentration data in individual pharmacokinetics. The proposed optimal design criterion minimizes the determinant of the mean-squared error matrix of the parameter estimator that is quadratically approximated by the curvature array. Therefore, the proposed criterion considers the intrinsic and parameter-effects nonlinearity underlying the compartment model, and so is applicable in a pharmacokinetic experiment where the sample size of the blood drug concentration data is quite small.

Effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats

The purpose of this study was to investigate the effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats. The blood concentration-time course and pharmacokinetic parameters of ciclosporin did not significantly change after intravenous injection of ciclosporin (10 mg kg(-1)) in rats treated with imatinib mesilate (50 mg kg(-1)) as compared with a control. When ciclosporin (10 mg kg(-1)) was orally administered, the time course, area under the curve, bioavailability and peak blood concentration of ciclosporin were significantly increased in rats that had been treated with imatinib mesilate 2 h before ciclosporin administration as compared with the control. Because both drugs are transported via P-glycoprotein and breast cancer resistance protein and metabolized by cytochrome P450 3A2, the interaction of imatinib mesilate with these proteins may be responsible for the increased intestinal absorption of ciclosporin in rats. These results indicate that imatinib mesilate enhanced the intestinal absorption of ciclosporin in rats with only the oral administration of ciclosporin, suggesting that our results support clinical data. In addition, imatinib mesilate may increase the pharmacological effects and possibly toxicity of ciclosporin.

Pharmacokinetic Analysis of the Tissue Distribution of Octaarginine Modified Liposomes in Mice

We recently found that octaarginine modified liposomes (R8-Lip) can be efficiently internalized by cultured cells. The purpose of the present study was to quantitatively determine the effect of R8-density on the tissue distribution of R8-Lip in mice, using their clearance as an index. R8 was introduced in the form of stearylated R8 (STR-R8). The liposomes were composed of cholesterol and egg phosphatidylcholine and were labeled with [(3)H]cholesteryl hexadecyl ether. Various densities of R8 (3%, 10% and 30%) containing liposomes were prepared with a diameter of approximately 70-80 nm. The tissue distribution of R8-Lip was determined after their i.v. administration into mice and the effect of R8-density on tissue distribution was compared with uptake clearance, the calculated tissue distribution divided by the area under the blood concentration-time course. As results, R8-Lip were more rapidly eliminated from circulating blood and distributed to many tissues, especially liver depending on the R8-density. However, the tissue uptake clearance represented similar value to that of positively charge liposomes. Based on these results, we conclude that the R8-dependent increase in R8-Lip in various tissues tested indicates that positive charge, but not PTD function derived from R8 predominantly responsible for the enhancement of tissue distribution. Therefore, it is suggested that topology control of R8 is important to exhibit the PTD function.

Role of variability in explaining ethanol pharmacokinetics: research and forensic applications.

Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of absorption of ethanol from the gut depends on time of day, drinking pattern, dosage form, concentration of ethanol in the beverage, and particularly the fed or fasting state of the individual. During the absorption phase, a concentration gradient exists between the stomach, portal vein and the peripheral venous circulation. First-pass metabolism and bioavailability are difficult to assess because of dose-, time- and flow-dependent kinetics. Ethanol is transported by the bloodstream to all parts of the body. The rate of equilibration is governed by the ratio of blood flow to tissue mass. Arterial and venous concentrations differ as a function of time after drinking. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences in disposition. The bulk of ethanol ingested (95-98%) is metabolised and the remainder is excreted in breath, urine and sweat. The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1 g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero-order elimination operates for a large part of the blood-concentration time course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme, cytochrome P450 2E1, has a higher Km (0.5-0.8 g/L) and is also inducible, so that the clearance of ethanol is increased in heavy drinkers. Study design influences variability in blood ethanol pharmacokinetics. Oral or intravenous administration, or fed or fasted state, might require different pharmacokinetic models. Recent work supports the need for multicompartment models to describe the disposition of ethanol instead of the traditional one-compartment model with zero-order elimination. Moreover, appropriate statistical analysis is needed to isolate between- and within-subject components of variation. Samples at low blood ethanol concentrations improve the estimation of parameters and reduce variability. Variability in ethanol pharmacokinetics stems from a combination of both genetic and environmental factors, and also from the nonlinear nature of ethanol disposition, experimental design, subject selection strategy and dose dependency. More work is needed to document variability in ethanol pharmacokinetics in real-world situations.

EFFECT OF POLYCYCLIC AROMATIC HYDROCARBONS ON THE ELIMINATION KINETICS OF PYRENE AND THE URINARY EXCRETION PROFILE OF 1-HYDROXYPYRENE IN THE RAT

Pyrene was chosen as a noncarcinogen model of polycyclic aromatic hydrocarbons (PAHs). Groups of male Wistar rats were dosed with pyrene and with mixture of pyrene and fluoranthene, pyrene and benz\\[a]anthracene, or pyrene, fluoranthene, and benz\\[a]anthracene at 20 mg/kg by intravenous or oral routes. Blood samples were taken at 0.25, 0.5, 1, 2, 3, 4, and 5 h after administration. The concentration of pyrene was determined by gas chromatography. The toxicokinetic parameters for pyrene were determined from the time course of blood concentration. A significant increase in the bioavailability of pyrene after treatment with other PAHs was observed. Urinary 1-hydroxypyrene excretion was analyzed after pretreatment with acenaphthene, naphthalene, chrysene, phenanthrene, benz\\[a]anthracene, and benzo\\[a]pyrene. The urine from rats was collected for 3 d and the concentration of 1-hydroxypyrene was determined using high-performance liquid chromatography (HPLC). Most compounds examined caused a decrease in the urinary excretion of the metabolite of pyrene.

Harman and Norharman in Alcoholism: Correlations with Psychopathology and Long‐Term Changes

In the search for mechanisms specific for alcoholism, it has become evident that beta-carbolines (BCs; e.g., harman and norharman) are compounds that may act on brain reward systems, thereby mediating an increase in voluntary ethanol (ETOH) drinking in animals. This study was undertaken to analyze relationships between these compounds and clinical variables (e.g., family history, personality data, and affect) in alcoholics and to trace the time course of blood concentrations in subjects abstaining from alcohol for at least 6 months. Nonalcoholics were investigated during sober and ETOH-loading conditions (1 g ETOH/kg body weight). Levels of harman were elevated in the chronically intoxicated alcoholics and correlated with the scores on the self-rating depression (SDS) and the self-rating anxiety (SAS) scales. The group of alcoholics with at least one alcoholic parent had higher levels than the group without such a history. Levels remained elevated for 6 months. Norharman levels were only slightly elevated on the day of admission. They were correlated to high harm avoidance and SDS scores. A family history of alcoholism and the severity of alcoholism as assessed by the number of ICD-10 criteria fulfilled were correlated with norharman levels. Long-term observation revealed elevated levels of norharman after 3 months of abstinence, but not after 6 months. The association of harman levels with anxiety and depression demonstrated in the present study suggests that alcoholics with high harman levels use alcoholic beverages as self-medication in an attempt to overcome possible anxiogenic/depressiogenic actions of harman. Norharman levels are less strongly associated with these mood states, but significantly correlated to harm avoidance tendencies. It has been suggested that the activity of the indolergic neurons is relatively high in individuals with a high harm avoidance score. Biosynthesis of norharman might be stimulated under these conditions (tryptamine serves as precursor).

Effects of ascorbic acid on iproniazid-induced hepatitis in phenobarbital-treated rats.

The effects of ascorbic acid (AA) on hepatic injury induced by iproniazid (IPN) in phenobarbital-treated rats were investigated by the evaluation of hepatic function using the clearance of aminopyrine (AM). Either IPN or isopropylhydrazine (IP-Hy), a potent toxic metabolite of IPN, were administered as a pretreatment to rats with or without AA. After i.v. injection of AM, the blood concentration of AM was determined by capillary gas chromatography by isotope dilution analysis using deuterium-labeled AM (AM-d9) as the internal standard. The kinetic parameters of AM, Vd, kel and total body clearance, were estimated from the time course of blood concentration. Pretreatment with IPN with AA led to a marked increase in the kel and in the clearance compared with pretreatment using IPN alone. A significant increase in the kel and the clearance was also found in the case of combined pretreatment using IP-Hy with AA. The effects of AA on the hepatic injury induced by IPN were studied according to its histological aspects. In the specimens obtained following the administration of IPN or IP-Hy with AA, the degree of cell necrosis was remarkably lowed both quantitatively and qualitatively. The present results clearly demonstrate that AA was effective in reducing IPN-induced hepatitis.

A pharmacokinetic model for the disposition of polychlorinated biphenyls (PCBs) in channel catfish

Channels catfish, Ictalurus punctatus, acclimated to 18°C, with mean body weight of 0.36 kg, were fitted with a cannula in the dorsal aorta. An intraaortic bolus injection of 50 μg/kg 14C polychlorinated biphenyls (PCBs) (42% w/w chlorine) was administered to five fish. Blood samples were withdrawn up to 96 h. The blood concentration-time course showed a triexponential decline with a rapid initial distributive phase and a slow terminal elimination phase. A three compartment model comprising of a central, shallow peripheral, and a deep peripheral compartment, adequately described the kinetics of PCBs in catfish. The whole body clearance (Cl b) was estimated to be 19.6 ml/h/kg and the volume of distribution at steady state ( V ss) was 1196.8 ml/kg. The terminal elimination half-life ( t 1 2 ) of PCBs in catfish was found to be 55.9 h. Computer simulations based on the developed model indicated that the majority of PCBs in the fish are associated with tissues of the deep peripheral compartment (i.e. adipose tissue).

Studies on biological fate of 14C-trazodone hydrochloride in rats.

Absorption, distribution and excretion of trazodone hydrochloride, a new antidepressant, after single and repeated oral administration in rats were studied using 14C-labelled drug (14C-trazodone hydrochloride). After single dose (4 mg/kg), the concentration of radioactivity in blood increased rapidly in male and female rats, suggesting rapid absorption of this drug. Similarly, tissue levels of radioactivity were immediately increased after the administration and declined thereafter without delay, which was consistent with the results of wholebody autoradiography. Urinary and fecal excretion during 96 hours was 38.6 and 60.1 % of total ingested radioactivity, respectively. At least 72.9 % of radioactivity excreted in bile was shown to be reabsorbed, which suggested significant contribution of enterohepatic circulation to time course of blood concentration. Concentration of radioactivity in the milk of lactating rats was slightly higher than that in the blood. Plasma protein binding of 14C-tradozone was shown to be constant within the concentration range studied in both in vitro and in vivo, although a large difference in fraction bound (88.7-89.9 % and 33.1-41.5 % for in vitro and in vivo, respectively) was found. After repeated oral dose (4 mg/kg/day), values of Cmax, AUC and T1/2 in blood concentration and tissue levels of radioactivity tended to increase with increasing administration period. However, values of tissue-to-plasma concentration ratio and the minimum blood concentration after each administration had reached the steady-state after 14 th administration. Ratio of radioactivities excreted into urine and feces was not so much changed by multiple dosing.

Tracer disposition kinetics in the determination of local cerebral blood flow by a venous equilibrium model, tube model, and distributed model.

Tracer distribution kinetics in the determination of local cerebral blood flow (LCBF) were examined by using three models, i.e., venous equilibrium, tube, and distributed models. The technique most commonly used for measuring LCBF is the tissue uptake method, which was first developed and applied by Kety (1951). The measurement of LCBF with the 14C-iodoantipyrine (IAP) method is calculated by using an equation derived by Kety based on the Fick's principle and a two-compartment model of blood-tissue exchange and tissue concentration at a single data point (Sakurada et al., 1978). The procedure, in which the tissue is to be in equilibrium with venous blood, will be referred to as the tissue equilibration model. In this article, effects of the concentration gradient of tracer along the length of the capillary (tube model) and the transverse heterogeneity in the capillary transit time (distributed model) on the determination of LCBF were theoretically analyzed for the tissue sampling method. Similarities and differences among these models are explored. The rank order of the LCBF calculated by using arterial blood concentration time courses and the tissue concentration of tracer based on each model were tube model (model II) less than distributed model (model III) less than venous equilibrium model (model I). Data on 14C-IAP kinetics reported by Ohno et al. (1979) were employed. The LCBFs calculated based on model I were 45-260% larger than those in models II or III. To discriminate among three models, we propose to examine the effect of altering the venous infusion time of tracer on the apparent tissue-to-blood concentration ratio (lambda app). A range of the ratio of the predicted lambda app in models II or III to that in model I was from 0.6 to 1.3. In the future, there may be a need to determine which model should be used to calculate the LCBF based on this discriminator and to develop another discriminator by using multiple data points based on positron emission tomography.

Opioid pharmacokinetics in relation to their effects.

The chemical structure of drug molecules determines their fundamental pharmacological properties by 'fit' to the receptor, but the physicochemical properties, particularly lipid solubility and fraction un-ionised, dominate in determining distribution in the body and the rate of access to the biophase containing the drug receptors. For example, fentanyl appears much more potent than morphine because similar effective biophase concentrations are achieved with much smaller doses. Pharmacokinetic and pharmacodynamic investigations of the relationships between dose and the time-courses of blood concentrations and pharmacological effects of opioid drugs have helped explain the commonly observed variability between patients and have been useful in deriving effective dosage regimens of opioids such as pethidine, morphine, fentanyl and methadone where blood concentrations are a determinant of pharmacological response and 'target' analgetic blood opioid concentrations have been identifiable. However, there are instances when blood opioid concentrations are not determinants of the analgetic response. Examples include opioids, such as buprenorphine, for which the drug-receptor dissociation rate determines the duration of action, heroin which first has to be metabolised to become an agonist, pentazocine which is an agonist at some opioid receptors and an antagonist at others, and opioids placed intra-spinally acting on receptors in the spinal cord.

Pharmacokinetic studies on 1-(2-chloroethyl)-3-isobutyl-3-(.BETA.-maltosyl)-1-nitrosourea (TA-077). III. Pharmacokinetics of a new nitrosourea antitumor agent TA-077 in humans (a phase I study).

A new nitrosourea antitumor agent TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, was intravenously administered to 15 cancer patients at doses ranging from 7 to 100 N (1 N = 30 mg/m2) in a phase I clinical trial. Time courses of blood concentrations of TA-077 and its active metabolite TA-G, 3-beta-D-glucopyranosyl analog of TA-077, were followed. The TA-G concentration reached a maximum at 7.0 +/- 2.3 min, and decreased thereafter with a half-life of 12.9 +/- 2.8 min. The time-course patterns and various pharmacokinetic parameters of TA-077 and TA-G were similar to those in the guinea pig, which, like humans, lacks plasma maltase activity. The 2 h-urinary excretion rate of TA-G in the above patients ranged from 0.15 to 7.7% of the dose. The areas under the concentration-time curve and maximal concentration values were both linearly correlated to the dose with correlation coefficients of 0.78 and 0.82, respectively. Repeated administration of TA-077 (29 to 40 N) for 5 or 6 consecutive days did not affect the pharmacokinetic parameters of TA-077 and TA-G in 7 cancer patients except for slight increases in the half-life and area under the curve of blood TA-G.

Comparative toxicity and biotransformation of lindane in C57BL/6 and DBA/2 mice

DBA/2 mice, previously identified as “unresponsive” to aromatic hydrocarbons which induce microsomal enzymes in C57BL/6 mice, are more vulnerable to the convulsant effect of repeated doses of lindane than similarly treated C57BL/6 mice. Death in convulsions and higher blood and brain lindane concentrations indicate that less efficient disposition of lindane itself accounts for the greater vulnerability of the DBA/2 mice. The same two principal chlorophenolic metabolites of lindane were identified in the blood and tissues of both strains, but the time-courses of blood concentrations in response to repeated lindane dosing were different.

On pharmacokinetics in target tissues.

Based on a two-compartment organ model the total exposure in a target tissue, the mean tissue residence time and the peak time of the tissue concentration are evaluated in terms of tissue to blood partition coefficient and permeability coefficient (membrane permeability) of the drug, as well as the organ volume and blood flow. The total exposure is dependent upon the partition coefficient whereas the mean residence time is also affected by the permeability coefficient of the target organ. The peak time of tissue concentration following bolus intravenous injection appears to be mainly determined by the mean organ transit time and the time course of blood concentration. A tissue specific therapeutic ratio is defined using the concept of total exposure and the advantages of a local route of drug administration are discussed in this respect.

Physiological pharmacokinetic model for distribution and elimination of pentazocine. II. Study in rabbits and scale-up to man

A physiologically based pharmacokinetic model was applied to describe the distribution and elimination of pentazocine in rabbits. For the elimination of pentazocine, the model consisted of renal, hepatic (metabolic and biliary), and GI secretion and Gl re-absorption. The tissue-to-blood partition coefficients of pentazocine in the rabbit were almost the same with those in the rat. No significant variation in hepatic blood flow rate dependent on the arterial blood concentration of pentazocine was observed in the rabbit, the results being very different from those in the rat. The time course of blood concentration after intravenous injection was proportional to dose in the range of 0.5–10 mg/kg. Excellent agreements were obtained between the predicted and observed concentrations of pentazocine after intravenous administration in the rabbit. Application of the rabbit model to prediction in man by considering the differences in organ volume, organ blood flow and renal pentazocine clearance was successful, and the model was adopted to decide the therapeutic dose of pentazocine during surgery of patients.

Moments of physiological transit time distributions and the time course of drug disposition in the body.

Characterizing the tissue distribution kinetics of drugs by physiological and physico-chemical parameters and using a circulatory model the time course of blood concentration after intravenous injection is predicted for linear pharmacokinetic systems. The interrelationships between the first three (zero to second) moments of the distribution functions of organ transfer times, circulation times and residence times of drug molecules in the body are described. Utilizing literature data the model is applied to the analysis of lidocain kinetics in humans.