A minimal physiological model of thiopental distribution kinetics based on a multiple indicator approach.

Currently available models of thiopental disposition kinetics using only plasma concentration-time data neglect the influence of intratissue diffusion and provide no direct information on tissue partitioning in individual subjects. Our approach was based on a lumped-organ recirculatory model that has recently been applied to unbound compounds. The goal was to find the simplest model that accounts for the heterogeneity in tissue partition coefficients and accurately describes initial distribution kinetics of thiopental in dogs. To ensure identifiability of the underlying axially distributed capillary-tissue exchange model, simultaneously measured disposition data of the vascular indicator, indocyanine green, and the marker of whole body water, antipyrine, were analyzed together with those of thiopental. A model obtained by grouping the systemic organs in two subsystems containing fat and nonfat tissues, successfully described all data and allowed an accurate estimation of model parameters. The estimated tissue partition coefficients were in accordance with those measured in rats. Because of the effect of tissue binding, the diffusional equilibration time characterizing intratissue distribution of thiopental is longer than that of antipyrine. The approach could potentially be used in clinical pharmacokinetics and could increase our understanding of the effect of obesity on the disposition kinetics of lipid-soluble drugs.     

Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients

The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89 min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16 l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.     

Residence Time Dispersion as a General Measure of Drug Distribution Kinetics: Estimation and Physiological Interpretation

Purpose To evaluate distribution kinetics of drugs by the relative dispersion of disposition residence time and demonstrate its uses, interpretation and limitations. Materials and Methods The relative dispersion was estimated from drug disposition data of inulin and digoxin fitted by three-exponential functions, and calculated from compartmental parameters published for fentanyl and alfentanil. An interpretation is given in terms of a lumped organs model and the distributional equilibration process in a noneliminating system. Results As a measure of the deviation from mono-exponential disposition (one-compartment behavior), the relative dispersion provides information on the distribution kinetics of drugs, i.e., diffusion-limited distribution or slow tissue binding, without assuming a specific structural model. It also defines the total distribution clearance which has a clear physical meaning. Conclusion The residence time dispersion is a model-independent measure that can be used to characterize the distribution kinetics of drugs and to reveal the influence of disease states. It can be estimated with high precision from drug disposition data.     

Influence of short-term water deprivation on antipyrine disposition

The effects of acute (96 h) water deprivation on the disposition kinetics of antipyrine and hepatic cytochrome P-450 content were investigated in male rats. The disposition kinetics of antipyrine in rats deprived of water for 96 h was altered significantly: the total body clearance and steady-state volume of distribution decreased by 27.1 and 22.4%, respectively, as compared to control rats. There was no significant change in the disposition rate constant as a result of simultaneous changes in the volume of distribution and clearance. There was a 51.4% decrease in the hepatic cytochrome P-450 content in water-deprived rats. These results suggest that the pharmacokinetic changes observed in acute water deprivation with a model drug, antipyrine, are related to a decrease in total body water and to a reduced amount and/or activity of the hepatic microsomal oxidative enzymes.     

Estimation of intradermal disposition kinetics of drugs: II. Factors determining penetration of drugs from viable skin to muscular layer

To develop a more efficient transdermal delivery system, it is very important to regulate the intradermal disposition of drugs after topical application. We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics. In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle (CL(vs-m)) was found to be significantly correlated with the unbound fraction of drugs in the viable skin (fu(vs)). Although the clearance from the viable skin to the plasma (CL(vs-p)) also tended to increase as fu(vs) increased, the ratio of CL(vs-m) to CL(vs-p) was significantly correlated with fu(vs), meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k(direct) values obtained in in vitro penetration study-the penetration rate constant of drugs from the viable skin to the muscular layer-were found to be correlated with CL(vs-m) values for seven model drugs. Therefore, adding the in vitro experiments for the other three model drugs, the multiple linear regression analysis of k(direct) was performed for ten model drugs in terms of fu(vs), logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu(vs) to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu(vs) in the viable skin can penetrate more into the muscular layer.     

Estimation of Intradermal Disposition Kinetics of Drugs: I. Analysis by Compartment Model with Contralateral Tissues

Purpose. The objectives of dermal application of drugs are not only systemic therapeutics, but also local ones. We would expect its intradermal kinetics to be dependent on its therapeutic purpose. To develop more efficient drugs for local or systemic therapeutics, it will be important to estimate quantitatively the intradermal disposition of drugs applied topically. We tried, therefore, to develop the compartment model to describe the intradermal disposition kinetics after topical application of drugs. Methods. In vivo percutaneous absorption study for antipyrine, a model compound, was performed using rats with tape-stripped skin, using the assumption that the stratum corneum permeability to drugs would be improved enough not to be a rate-limiting process. Results. To analyze the results obtained, a 4-compartment model, composed of donor cell, viable skin, muscle, and plasma compartments, was applied. Although the fitting lines obtained could describe the concentration-time profiles of antipyrine in each compartment very well, the concentration profiles in the contralateral tissues were extensively overestimated. Therefore, we developed a 6-compartment model which included the viable skin and muscle in the contralateral site, and analyzed the concentration-time curve of each compartment. The fitting curves were in good agreement with the experimental data for all the compartments including the contralateral viable skin and muscle, and thus, this model was recognized to be adequate for the estimation of intradermal kinetics after topical application. Judging from the obtained values of clearance from viable skin to plasma and from viable skin to muscle, about 80% of antipyrine penetrated into viable skin, which suggested it was absorbed into circulating blood and 20% was transported to muscle under viable skin. Conclusions. Pharmacokinetic analysis using the 6-compartment model would be very useful for the estimation of local and systemic availability after topical application of drugs.     

A Recirculatory Model of the Pulmonary Uptake and Pharmacokinetics of Lidocaine Based on Analysis of Arterial and Mixed Venous Data from Dogs

Pulmonary uptake of basic amine xenobiotics such as lidocaine may influence the onset of drug effect and ameliorate toxicity. To date, pharmacokinetic analysis of pulmonary drug uptake has been only semiquantitative and ill-suited for relating pharmacodynamics to pharmacokinetics or jar estimating the time course of the fraction of drug dose residing in the lung during a single pass. We have developed recirculatory models in an experiment in which lidocaine was injected into the right atrium simultaneously with markers of intravascular space (indocyanine green) and total body water (antipyrine): this was followed by rapid arterial and mixed venous blood sampling. Such models are interpretable physiologically and are capable of characterizing the kinetics of the pulmonary uptake of lidocaine in addition to peripheral tissue distribution and elimination. The apparent pulmonary tissue volume of lidocaine (39 ml/kg) was nearly ninefold greater than that of antipyrine (4.5 ml/kg). The recirculatory model characterized both arterial and mixed venous data, but the latter data were not essential for estimating lidocaine's pulmonary disposition either before or after recirculation of drug was evident.     

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis

The approach presented enables a model independent representation of the pharmacokinetics of drugs with a liner disposition and some drugs with a nonlinear disposition. The approach is based on a decomposition of the drug disposition into an elimination function q(c) and a distribution function h(t). The q function represents the net effect of all disposition processes which work toward a reduction in the systemic drug level. The h function represents the net effect of all disposition processes which slow down the rate of decline of the systemic drug level by returning drug from the peripheral environment to the systemic circulation. Several theorems relating q and h to the drug disposition are presented which uniquely define these functions mathematically. The disposition decomposition is of particular significance in three main areas of pharmacokinetics: (1) evaluation of drug absorption, (2) drug level predictions including steady state predictions, (3) and elucidation of drug disposition kinetics. The practical significance of the decomposition method in these three areas is discussed, and various procedures for the application of the method are proposed. The decomposition method represents a model independent alternative to pharmacokinetic models such as linear compartmental models, the recirculation model, and some physiologic models. This also includes nonlinear forms of such models, as long as the nonlinearity is due to a central nonlinear elimination. The greatest promise and significance of the disposition decomposition approach appears to be its application to nonlinear pharmacokinetics. In contrast to linear pharmacokinetics the kinetic analysis in such cases has been limited to model dependent methods employing specific pharmacokinetic models, due to the lack of model independent alternatives. The novel development presented offers such alternatives. For some applications these alternatives appear more rational in the sense that the analysis becomes more general and objective and may be based on fewer assumptions.     

Absence of changes in drug disposition and catecholamine sensitivity in the hyperthyroid dog.

1 In order to study the relative contribution of hepatic drug metabolizing enzymes and hepatic blood flow to the clearance of drugs in the hyperthyroid state, the disposition kinetics of two model compounds (antipyrine and propranolol) were examined in thyroid-fed dogs as compared to euthyroid and phenobarbitone-pretreated animals. 2 In hyperthyroid dogs, the possibility of catecholamine hypersensitivity was evaluated by assessing the chronotropic response to isoprenaline and by constructing a drug concentration-effect (beta-blockade) relationship. 3 The plasma propranolol half-life (0.97 +/- 0.12 h) of the hyperthyroid animals did not differ significantly from either the euthyroid group or the phenobarbitone-pretreated group. This was observed with no significant change in the apparent volume of distribution among the three experimental groups. 4 Phenobarbitone pretreatment accelerated significantly the elimination of antipyrine (half-life, 1.09 +/- 0.15 h, P less than 0.01) as compared to the euthyroid (2.84 +/- 0.35 h) and the hyperthyroid groups (2.58 +/- 0.13 h), respectively, without any changes in the apparent volume of distribution in any group. 5 Neither the chronotropic responses to exogenously administered catecholamine, nor the antagonist concentration-effect relationships support the concept that the hyperthyroid state potentiates sensitivity of the receptor-effect system of the heart. 6 The data obtained from the present study fit best with the view that thyroid hormone excess alters neither the disposition of the model compounds used nor the catecholamine-sensitivity examined.     

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis

The approach presented enables a model independent representation of the pharmacokinetics of drugs with a linear disposition and some drugs with a nonlinear disposition. The approach is based on a decomposition of the drug disposition into an elimination function q(c) and a distribution function h(t). The qfunction represents the net effect of all disposition processes which work toward a reduction in the systemic drug level. The hfunction represents the net effect of all disposition processes which slow down the rate of decline of the systemic drug level by returning drug from the peripheral environment to the systemic circulation. Several theorems relating qand hto the drug disposition are presented which uniquely define these functions mathematically. The disposition decomposition is of particular significance in three main areas of pharmacokinetics: (1) evaluation of drug absorption, (2) drug level predictions including steady state predictions, and (3)elucidation of drug disposition kinetics. The practical significance of the decomposition method in these three areas is discussed, and various procedures for the application of the method are proposed. The decomposition method represents a model independent alternative to pharmacokinetic models such as linear compartmental models, the recirculation model, and some physiologic models. This also includes nonlinear forms of such models, as long as the nonlinearity is due to a central nonlinear elimination. The greatest promise and significance of the disposition decomposition approach appears to be its application to nonlinear pharmacokinetics. In contrast to linear pharmacokinetics the kinetic analysis in such cases has been limited to model dependent methods employing specific pharmacokinetic models, due to the lack of model independent alternatives. The novel development presented offers such alternatives. For some applications these alternatives appear more rational in the sense that the analysis becomes more general and objective and may be based on fewer assumptions.     

Transplacental transfer of acrylamide and glycidamide are comparable to that of antipyrine in perfused human placenta

Most drugs can penetrate the placenta but there are only a few studies on placental transfer of environmental toxic compounds. In this study, we used dual recirculating human placental perfusion to determine the transfer rate through the placenta of a neurotoxic and carcinogenic compound found in food, acrylamide and its genotoxic metabolite glycidamide. Putative acrylamide metabolism into glycidamide during the 4-h perfusions and acrylamide-derived DNA adducts in placental DNA after perfusions were also analyzed. Placentas were collected immediately after delivery and kept physiologically functional as confirmed by antipyrine kinetics, glucose consumption and leak from fetal to maternal circulation. Acrylamide (5 or 10 microg/ml) or glycidamide (5 microg/ml), both with antipyrine (100 microg/ml), was added to maternal circulation. Acrylamide and glycidamide were analyzed in the perfusion medium by liquid chromatography/mass spectrometry. Acrylamide and glycidamide crossed the placenta from maternal to fetal circulation with similar kinetics to antipyrine, suggesting fetal exposure if the mother is exposed. The concentrations in maternal and fetal circulations equilibrated within 2h for both studied compounds and with both concentrations. Acrylamide metabolism into glycidamide was not detected during the 4-h perfusions. Moreover, DNA adducts were undetectable in the placentas after perfusions. However, fetuses may be exposed to glycidamide after maternal metabolism. Although not found in placental tissue after 4h of perfusion, it is possible that glycidamide adducts are formed in fetal DNA.     

Saturable, non-Michaelis-Menten uptake of liposomes by the reticuloendothelial system.

Multilamellar vesicles (300-350 nm) were infused into the rat femoral vein at the rate of 4, 40 and 400 nmol phosphatidycholine min-1 for 6 h using [3H]inulin as an aqueous marker. The time courses of blood concentration of vesicles, normalized for infusion rate, were not superimposable, showing the non-linearity of liposome disposition in the blood circulation. These time courses of blood concentration were well fitted by a single Michaelis-Menten equation. On the other hand, the time courses of tissue content could not be so accommodated. Additionally, the observed relationship between the uptake of liposomes by the liver and their clearance from it and other organs differed essentially from a simulation based on Michaelis-Menten type saturable kinetics. Therefore, it is suggested that there is a time-dependent non-Michaelis-Menten type process in the phagocytosis of macrophages in the reticuloendothelial system.     

Use of parallel erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog. Supported in part by the National Institute of General Medical Sciences RO1-GM-43776, RO1-GM-47502, and PO1-GM-47819.     

The Effect of Antineoplastic Drugs on the Pharmacokinetics of Antipyrine in the Rat

Abstract: The pharmacokinetics of antipyrine was investigated in individual rats pretreated with cyclophosphamide, 5-fluorouracil and methotrexate. Before oral dosing a complete emptying of the rat stomach was obtained by 24 hours of fasting and prevention of coprophagy. Antipyrine was given intravenously via a cannula in an inguinal vein and repeated samples of blood were drawn from a cannula in an inguinal artery. Systemic availability of oral antipyrine was studied in rats given the ¹⁴C-labelled drug intravenously and the ³H-labelled drug orally after pretreatment with cyclophosphamide. The log plasma concentration versus time curve of antipyrine given orally showed a short absorption and distribution phase followed by a linear elimination phase. Peak antipyrine concentrations were reached 3–6 minutes after oral dosing in control rats. The rate of absorption of antipyrine was moderately decreased by methotrexate. All drugs increased the area under the curve (AUC) of antipyrine. The systemic availability of oral antipyrine after cyclophosphamide pretreatment (0.88) was not changed, but the metabolic clearance of the drug was reduced. The apparent elimination rate constant was decreased by methotrexate and the apparent volume of distribution was decreased by cyclophosphamide and 5-fluorouracil. The results indicate that antineoplastic agents may change drug kinetics in different ways in rats.     

Antipyrine kinetics in undernourished diabetics

Summary In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insulin dependent diabetes (NIDDM) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits.The AUC of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes per se may not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.     

Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT)

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaike's information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (Fc) and the mean circulatory time (-tc) through a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (Fa) and the mean absorption time (-tc) for the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (Fb) and the mean transit time (-tb) for the disposition process through the systemic circulation into the bile were 40.8% and 1.05 hr, respectively.     

The effect of fenfluramine on disposition and rate of antipyrine elimination.

The effect of fenfluramine, administered orally in a daily dose of 1 mg/kg for 40 days, on the disposition and rate of elimination of antipyrine was studied in 15 obese patients. Although the plasma half-life of antipyrine was unchanged, the apparent volume of distribution (1/kg) fell by 11.6% (p less than 0.001) and the plasma metabolic clearance rate (1/kg/h) of antipyrine was reduced by 14.1% (p less than 0.01). No correlation occurred between change in clearance, on the one hand, and change in patient weight or apparent volume of distribution of antipyrine, on the other. In vitro drug-metabolizing enzyme activity in the rat was measured using rate of aminopyrine and hexobarbital metabolism as indices. Fenfluramine inhibited the metabolism of both substrates. It is concluded that fenfluramine can diminish the rate of elimination of drugs which are extensively metabolized by reduction of microsomal enzyme activity. Also, drug clearance may be diminished by reduction of apparent volume of distribution.     

Effects of cardiac output on disposition kinetics of sorbitol: recirculatory modelling

1   The purpose of this study was to determine the effects of cardiac output on distribution and elimination kinetics of the marker compound sorbitol.
2   The disposition kinetics of sorbitol were investigated after rapid intravenous injection and arterial sampling in nine patients who had undergone cardiac catheterization whereby the cardiac output was measured.
3   A minimal circulatory model consisting of pulmonary and systemic subsystems, both of which were characterized by an inverse Gaussian transit time density function, fitted the data very well. The method involves numerical inverse Laplace transform of the model equations.
4   The mixing clearance introduced as a novel non-compartmental parameter of distribution dynamics was significantly correlated with cardiac output. The steady-state volume of 14 l matched the extracellular volume. The systemic extraction ratio of 23% may reflect the fractional liver blood flow.
5   This pharmacokinetic model can be applied when an independent observation of cardiac output is available. In contrast to the conventional compartmental (or sum of exponential) approach it contains fewer adjustable parameters which can be more readily interpreted in physiological terms.     

Dermatopharmacokinetics of salicylate following topical injection in rats: effect of osmotic pressure and injection volume on salicylate disposition

Using advanced topical formulations containing potential chemical enhancer(s) or physical penetration-enhancing tools capable of delivering entrapped drug(s) directly into skin tissues with little influence of the stratum corneum barrier, local and systemic drug disposition may be markedly similar to direct injection into the skin and muscle. The objective of this study is to investigate the dermatopharmacokinetics and systemic drug disposition after topical application and topical injection. Salicylate (SA) disposition in the skin and muscle as administration sites, and in the systemic circulation were evaluated following intracutaneous (i.c.) injection of an isotonic solution of SA-Na (dose; 3.08 micromol). Subcutaneous (s.c.) and intramuscular (i.m.) injection were also evaluated for comparison. Dermatopharmacokinetics and systemic disposition of SA after i.c. and s.c. injections were analyzed using a 4-compartment model consisting of skin, muscle, and central and peripheral compartments, whereas SA disposition after i.m. injection was analyzed using a 3-compartment model consisting of muscle, and central and peripheral compartments. Moreover, the absorption rate constant of SA after i.c. injection (0.073 min(-1)) was slightly lower than that after s.c. injection (0.083 min(-1)), and much lower than that after i.m. injection (0.327 min(-1)). In addition, higher osmolarity and a larger volume of SA-Na injectant increased the retention of SA in the skin and decreased the absorption rate to the systemic circulation after i.c. injection. The effect of injection volume on SA disposition after i.c. injection was not so marked compared with that of osmotic pressure. These results are useful to design an injection-type topical delivery system.