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What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations., Methods: S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses., Results: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(-) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(-) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01., Conclusions: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Knowledge of factors influencing the heterogeneity of blood transit times is important in cardiovascular physiology. The aim of the study was to investigate the effect of beta-adrenergic blockade on blood transit time dispersion in awake, anxious volunteers. Recirculatory modelling of the disposition of intravascular markers using parametric forms for transit time distributions, such as the inverse Gaussian distribution, provides the opportunity to estimate the systemic and pulmonary transit time dispersion in vivo. The latter is determined by the flow heterogeneity in the microcirculatory network. Using this approach, we have analysed indocyanine green (ICG) disposition data obtained in four subjects by frequent early arterial blood sampling before and after beta-adrenergic blockade by propranolol. Propranolol decreased cardiac output from 9·3 ± 2·8 l min -1 to 3·5 ± 0·47 l min -1 (P<0·05). This reduction was accompanied by a 4·5 ± 0·6-fold and 2·1 ± 0·3-fold increase (P<0·001) in the relative dispersion (dimensionless variance) of blood transit times through the systemic and pulmonary circulation, respectively., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Although indocyanine green (ICG) has long been used for the assessment of liver function, the respective roles of sinusoidal uptake and canalicular excretion in determining hepatic ICG clearance remain unclear. Here this issue was addressed by incorporating a liver model into a minimal physiological model of ICG disposition that accounts of the early distribution phase after bolus injection. Arterial ICG concentration-time data from awake dogs under control conditions and from the same dogs while anesthetized with 3.5% isoflurane were subjected to population analysis. The results suggest that ICG elimination in dogs is uptake limited since it depends on hepatocellular uptake capacity and on biliary excretion but not on hepatic blood flow. Isoflurane caused a 63% reduction in cardiac output and a 33% decrease in the ICG biliary excretion rate constant (resulting in a 26% reduction in elimination clearance) while leaving unchanged the sinusoidal uptake rate. The terminal slope of the concentration-time curve, K, correlated significantly with elimination clearance. The model could be useful for assessing the functions of sinusoidal and canalicular ICG transporters., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Although available therapies provide relief to many patients with cancer-related pain, swallowing difficulties or intestinal obstruction may preclude oral analgesic delivery in some. Topical morphine might provide an alternate delivery form but morphine bioavailability from a topical gel formulation has not been reported in humans. We conducted a randomized, placebo-controlled, double-blind, crossover study of five volunteers after they provided institutionally-approved, written, informed consent. They were admitted to the Northwestern University General Clinical Research Center twice, being randomly assigned to receive either 1mL of morphine compounded at 10mg/mL in pluronic lecithin organogel (PLO) base applied to the wrist and 1mL of normal saline administered subcutaneously, or 1mL of topical drug-free PLO base and 1mL of subcutaneous morphine, 3mg/mL, the first time and the opposite combination the second. Seventeen blood samples were collected from 5minutes to 10hours after dose administration for morphine concentration determination. Plasma samples were prepared by solid-phase extraction and morphine concentrations measured by a mass spectrometric technique with a linear range of 0.5-500ng/mL. Bioavailability of the topical formulation relative to the subcutaneous dose was to be estimated from doses and the plasma morphine concentration versus time relationships. Because morphine was seldom detected in plasma samples after topical administration and was unquantifiable when it was, the low bioavailability of topical morphine was unquantifiable. These results suggest that topical administration of morphine compounded in a PLO base for transdermal drug delivery is unlikely to provide relief of cancer-related pain.

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.

A pharmacokinetic model was developed to estimate physiologically meaningful parameters of distribution kinetics from plasma concentration-time data. The model is based on simultaneously measured disposition curves of drug and vascular marker. Employing residence time distribution theory, a recirculatory model with two subsystems, the pulmonary and systemic circulation, was constructed. In addition to intravascular mixing, the axially distributed model of the systemic circulation accounts for transcapillary transport of solutes, quantified by permeability-surface area product (PS) and diffusional equilibration time. Parameters of ICG, inulin, and antipyrine were estimated from disposition data obtained in awake dogs under control conditions and during an isoproterenol infusion or moderate hypovolemia. Results suggest that distribution kinetics is (1) governed by extravascular diffusion and (2) its dependency on cardiac output decreases with increasing diffusional resistance. Hemorrhage decreased the effective PS of inulin. In conclusion, this novel mechanistic model effectively described both the permeability-limited distribution of inulin into interstitial fluid and the flow-limited distribution of antipyrine into total body water and might be useful for other drugs., ((c) 2007 Wiley-Liss, Inc.)

A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.

We present an in vivo method for analyzing the distribution kinetics of physiological markers into their respective distribution volumes utilizing information provided by the relative dispersion of transit times. Arterial concentration-time curves of markers of the vascular space [indocyanine green (ICG)], extracellular fluid (inulin), and total body water (antipyrine) measured in awake dogs under control conditions and during phenylephrine or isoproterenol infusion were analyzed by a recirculatory model to estimate the relative dispersions of transit times across the systemic and pulmonary circulation. The transit time dispersion in the systemic circulation was used to calculate the whole body distribution clearance, and an interpretation is given in terms of a lumped organ model of blood-tissue exchange. As predicted by theory, this relative dispersion increased linearly with cardiac output, with a slope that was inversely related to solute diffusivity. The relative dispersion of the flow-limited indicator antipyrine exceeded that of ICG (as a measure of intravascular mixing) only slightly and was consistent with a diffusional equilibration time in the extravascular space of approximately 10 min, except during phenylephrine infusion, which led to an anomalously high relative dispersion. A change in cardiac output did not alter the heterogeneity of capillary transit times of ICG. The results support the view that the relative dispersions of transit times in the systemic and pulmonary circulation estimated from solute disposition data in vivo are useful measures of whole body distribution kinetics of indicators and endogenous substances. This is the first model that explains the effect of flow and capillary permeability on whole body distribution of solutes without assuming well-mixed compartments.

Beta-adrenergic receptor blockers decrease intravenous anesthetic dose requirements. The present study determined the effect of propranolol on indocyanine green and antipyrine disposition from the moment of rapid intravenous injection. Anti-pyrine is a physiological marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a pharmacokinetic surrogate for many lipophilic drugs, including intravenous anesthetics. Antipyrine and indocyanine green disposition were determined twice in five healthy adult males in this Institutional Review Board-approved study, once during propranolol infusion. After rapid indocyanine green and antipyrine injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma indocyanine green and antipyrine concentrations were measured by high-performance liquid chromatography. Indocyanine green and antipyrine disposition were characterized, using SAAM II, by a recirculatory pharmacokinetic model that describes drug disposition from the moment of injection. Parameters were compared using the paired t test. The disposition of indocyanine green demonstrated that propranolol decreased cardiac output at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area under the antipyrine concentration versus time relationship was doubled for at least the first 3 min after injection due to both decreased cardiac output and maintenance of nondistributive blood flow at the expense of a two-thirds reduction of blood flow (intercompartmental clearance) to the rapidly equilibrating (fast, splanchnic) tissue volume. The increase in antipyrine area under the curve due to propranolol-induced alteration of initial antipyrine disposition could explain decreased intravenous anesthetic dose requirements in the presence of beta-adrenergic receptor blockade.

Background: The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target., Methods: Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated., Results: Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters., Conclusions: Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.

Studies of factors affecting the initial disposition of drugs with a rapid onset of effect following i.v. administration have used antipyrine as a surrogate for lipophilic drugs because it lacks cardiovascular effects. The present study tested the assumption that antipyrine is a useful surrogate for the flow-dependent tissue distribution of the lipophilic drug thiopental by comparing the recirculatory pharmacokinetic models of antipyrine and thiopental disposition after concomitant administration to five dogs anesthetized with 1.5% halothane. The pharmacokinetics of indocyanine green, a marker of the intravascular behavior of antipyrine and thiopental, and antipyrine in these dogs was nearly identical to that described previously in dogs anesthetized with 1.5% halothane but not given thiopental. The total volume of distribution of the highly lipophilic drug thiopental was more than 60% larger than that of antipyrine, 53 versus 33 liters, respectively. Nonetheless, the initial distribution kinetics of the two drugs, including the pulmonary tissue volume and the volume of the nondistributive pathway as well as the clearance to it, were nearly identical. As a result, the fraction of cardiac output involved in distribution of the two drugs to peripheral tissues was similarly identical, although the distribution of cardiac output between clearance to the rapidly equilibrating tissues and clearance to the slowly equilibrating tissues differed slightly. This study validates the assumption that antipyrine is a useful surrogate for lipophilic drugs in pharmacokinetic studies in which physiologic stability is desirable to meet the assumption of system stationarity.

Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine facilitate description of intravascular mixing and tissue distribution following intravenous administration. These models characterized physiologic marker disposition in four awake dogs under control conditions and during phenylephrine, isoproterenol, and nitroprusside infusions. Systemic vascular resistance was more than doubled by phenylephrine and was decreased more than 50% by both isoproterenol and nitroprusside. Dye (ICG) dilution cardiac output (CO) was decreased nearly one-third by phenylephrine, was more than doubled by isoproterenol, and was largely unaffected by nitroprusside. Although phenylephrine reduced CO, the fraction of CO represented by nondistributive blood flow nearly doubled at the expense of blood flow to rapidly equilibrating tissues. The area under the blood antipyrine concentration versus time relationship for 3 min after administration (AUC(0-3 min)) during the phenylephrine infusion was nearly 75% larger than control due to both increased first-pass AUC and an increased fraction of CO represented by nondistributive blood flow. The large increase in CO produced by isoproterenol increased blood flow to rapidly equilibrating tissues and relatively decreased blood flow to slowly equilibrating tissues, because some appeared to equilibrate rapidly. Antipyrine AUC(0-3 min) during the isoproterenol infusion decreased more than 30%, due to decreased first-pass AUC. Nitroprusside changed antipyrine intercompartmental clearances in proportion to CO and, hence, had little effect on antipyrine AUC(0-3 min). These data provide further evidence that changes in antipyrine (a lipophilic drug surrogate) blood flow-dependent distribution after rapid i.v. administration are not proportional to changes in CO but depend on both CO and its distribution.

Background: Extensive pulmonary uptake of lipophilic basic amines, such as fentanyl, attenuates early blood drug concentrations after rapid intravenous administration. The basis of this phenomenon is poorly understood. The authors tested the hypothesis that fentanyl uptake into cultured human lung microvascular endothelial (HMVE-L) cells occurs by facilitated uptake in addition to passive diffusion. The authors compared fentanyl and alfentanil uptake with that of antipyrine, a diffusible marker of pulmonary tissue water. In addition, the authors determined the effect of verapamil, a nonspecific inhibitor of drug transport, and UIC2, a blocking antibody of the P-glycoprotein drug transporter, on the uptake of these drugs., Methods: Human lung microvascular endothelial cells were incubated, with varying concentrations of antipyrine and fentanyl or alfentanil in the absence or presence of varying verapamil concentrations or of UIC2. Supernatants were collected and cells were rinsed and dissolved. Supernatant and cell-associated antipyrine, fentanyl, and alfentanil concentrations were measured. The data were fit to a model of cellular uptake that allowed for passive diffusion and facilitated uptake., Results: Alfentanil uptake by HMVE-L cells was indistinguishable from that of antipyrine for the concentration ranges studied. In contrast, at low concentrations, fentanyl sequestration into HMVE-L cells was substantially greater than that of antipyrine. Facilitated fentanyl uptake was blocked by verapamil, but not by UIC2, in a concentration-dependent manner., Conclusions: The differential HMVE-L uptake of fentanyl and alfentanil is consistent with the observed differences in the pulmonary uptake of these drugs. This suggests that specific fentanyl uptake and sequestration by HMVE-L cells may be the mechanisms of its extensive pulmonary uptake.

Background: Earlier studies have demonstrated that physiologic marker blood concentrations in the first minutes after administration, when intravenous anesthetics exert their maximum effect, are determined by both cardiac output and its distribution. Given the reported vasodilating properties of isoflurane, we studied the effects of isoflurane anesthesia on marker disposition as another paradigm of altered cardiac output and regional blood flow distribution., Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1.7%, 2.6%, and 3.5% isoflurane (1.15, 1.7, and 2.3 minimum alveolar concentration, respectively) in a randomized order determined by a Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on very frequent early, and less frequent later, arterial blood samples. These models characterize the role of cardiac output and regional blood flow distribution on drug disposition., Results: Isoflurane caused a significant and dose-dependent decrease in cardiac output. Antipyrine disposition was profoundly affected by isoflurane anesthesia, during which nondistributive blood flow was maintained despite decreases in cardiac output, and the balance between fast and slow tissue volumes and blood flows was altered., Conclusions: The isoflurane-induced changes in marker disposition were different than those the authors reported previously for halothane anesthesia, volume loading, or hypovolemia. These data provide further evidence that not only cardiac output but also its peripheral distribution affect early drug concentration history after rapid intravenous administration.

Background and Objectives: Although indocyanine green can be used to estimate cardiac output and blood volume independently, a recirculatory multicompartmental indocyanine green model enables description of these and additional intravascular events. Our model was used to describe the effect of propranolol on blood volume and flow distribution in humans., Methods: Indocyanine green disposition was determined twice in four healthy adult men, once during a propranolol infusion that decreased cardiac output. After injection of indocyanine green, arterial blood was collected frequently for 2 minutes and less frequently thereafter. Plasma indocyanine green concentrations were measured by HPLC. The recirculatory pharmacokinetic model incorporates data from both the initial transient oscillations and the later post-mixing portions of the blood indocyanine green concentration versus time curves to characterize not only blood volume and cardiac output but also their distribution among a central blood volume and fast and slow peripheral volumes in lumped parallel circuits. Flow through the central circulation (cardiac output) is described by two parallel Erlang distribution functions generated by two linear chains of compartments in parallel., Results: Propranolol reduced cardiac output from 10.6 to 4.1 L/min. Most of the decrease in cardiac output was at the expense of blood flow to the fast peripheral circuit, which represented nonsplanchnic circulation. Propranolol also reduced the blood volume of the fast peripheral circuit by more than half., Conclusion: Our indocyanine green model is able to derive estimates of blood volume and cardiac output, as well as their systemic distribution during different physiologic conditions.

Recirculatory pharmacokinetic models for indocyanine green (ICG), inulin, and antipyrine describe intravascular mixing and tissue distribution after i.v. administration. These models characterized physiologic marker disposition in four awake, splenectomized dogs while they were normovolemic, volume loaded (15% of estimated blood volume added as a starch solution), and mildly and moderately hypovolemic (15 and 30% of estimated blood volume removed). ICG-determined blood volumes increased 20% during volume loading and decreased 9 and 22% during mild and moderate hypovolemia. Dye (ICG) dilution cardiac output (CO) increased 31% during volume loading and decreased 27 and 38% during mild and moderate hypovolemia. ICG-defined central and fast peripheral intravascular circuits accommodated blood volume alterations and the fast peripheral circuit accommodated blood flow changes. Inulin-defined extracellular fluid volume contracted 14 and 21% during hypovolemia. Early inulin disposition changes reflected those of ICG. The ICG and inulin elimination clearances were unaffected by altered blood volume. Neither antipyrine-defined total body water volume nor antipyrine elimination clearance changed with altered blood volume. The fraction of CO not involved in drug distribution had a significant effect on the area under the antipyrine concentration-versus-time relationships (AUC) in the first minutes after drug administration. Hypovolemia increased the fraction of CO represented by nondistributive blood flow and increased the antipyrine AUC up to 60% because nondistributive blood flow did not change, despite decreased CO. Volume loading resulted in a smaller (less than 20%) antipyrine AUC decrease despite increased fast tissue distributive flow because nondistributive flow also increased with increased CO.

Background: Differences in the pharmacokinetics of the enantiomers of ketamine have been reported. The authors sought to determine whether these differences extend to pulmonary uptake and peripheral tissue distribution and to test the hypothesis that tissue distribution of the stereoisomers differs because of carrier-mediated drug transport., Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green, ICG) and total body water and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)-ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0% halothane. Marker and drug dispositions were described by recirculatory pharmacokinetic models based on frequent early and less-frequent later arterial blood samples. These models characterize pulmonary uptake and the distribution of cardiac output into parallel peripheral circuits., Results: Plasma elimination clearance of the S-(+)-ketamine enantiomer, 29.9 ml x min(-1) x kg(-1), was higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x kg(-1). The apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l). The peripheral tissue distribution volumes and clearances and the total volume of distribution (2.1 l/kg) were the same for both stereoisomers when elimination clearances were modeled from the rapidly equilibrating peripheral compartment., Conclusions: Although the elimination clearance of S-(+)-ketamine is 35% greater than that of the R-(-)-enantiomer, there is no difference in the apparent pulmonary tissue volume or peripheral tissue distribution between the stereoisomers, suggesting that physicochemical properties of ketamine other than stereoisomerism determine its perfusion-limited tissue distribution.

Fentanyl is a basic amine shown to have extensive first-pass pulmonary uptake. To evaluate the role of the pulmonary endothelium in this uptake process, the simultaneous pharmacokinetics of [3H]fentanyl and two marker drugs, blue dextran, and [14C]antipyrine, were evaluated in a flow-through system of pulmonary endothelial cells. Fentanyl equilibrium kinetics were determined in a static culture system. The flow-through system consisted of monolayers of bovine pulmonary artery endothelial cells cultured on solid microcarrier beads placed in a chromatography column and perfused at 1.0 ml/min (37 degreesC). Fentanyl and the markers were injected into the perfusate at the top of the column and samples were collected from the eluate at 9-s intervals for 10 min. The pharmacokinetic analyses were based on determinations of mean transit time and flow. Fentanyl was partitioned into the pulmonary endothelial cells 60 times more than the tissue water space marker antipyrine. In the static system, monolayers of bovine pulmonary artery endothelial cells were cultured in 3.8-cm2 wells to which were added 0 to 946 micromol (0-500 microgram/ml) of unlabeled fentanyl citrate and 0.14 micromol of [3H]fentanyl. After a 10-min incubation, solubilized cells were assayed for [3H]fentanyl. Pulmonary endothelial cells contained a higher relative fentanyl concentration at lower fentanyl supernatant concentrations than would be expected if uptake occurred by diffusion alone. These observations can be explained with a model of fentanyl uptake that includes both passive diffusion and saturable active uptake. This suggests that the extensive first-pass pulmonary uptake of fentanyl observed in vivo is due largely to vascular endothelial drug uptake by both a passive and a saturable active uptake process.

Background: The cardiovascular effects of halothane are well recognized, but little is known of how this affects drug distribution. The effect of halothane anesthesia on physiologic factors that affect drug disposition from the moment of injection was investigated., Methods: The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1%, 1.5%, and 2% halothane in a randomized order determined by a repeated measures Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on frequent early and less frequent later arterial blood samples. These models characterize the role of cardiac output and its distribution on drug disposition., Results: Halothane caused a significant and dose-dependent decrease in cardiac output. The disposition of antipyrine was most profoundly affected by halothane anesthesia, which increased both nondistributive intercompartmental clearance and volume while decreasing fast and slow tissue clearances and elimination clearance in a halothane dose-dependent manner., Conclusions: Halothane-induced changes in blood flow to the compartments of the antipyrine recirculatory model were not proportional to changes in cardiac output. Halothane anesthesia significantly increased (to more than double) the area under the drug concentration versus time curve due to an increase in the apparent peripheral blood flow not involved in drug distribution, despite a dose-dependent cardiac output decrease. Recirculatory pharmacokinetic models include the best aspects of traditional compartmental and physiologic pharmacokinetic models while offering advantages over both.

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 for 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.

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.

Pharmacokinetic models were developed to describe the disposition of markers of extracellular fluid (inulin) and total body water (antipyrine) from the moment of injection to incorporate the intravascular mixing component, determined by a marker of intravascular space (indocyanine green, ICG). The simultaneous dispositions of these markers were characterized in four halothane-anesthetized dogs. After injection of ICG, [14C]-inulin, and antipyrine into the right atrium, femoral arterial blood samples were collected every 3 sec for 1 min and less frequently to 20 min for ICG and to 360 min for inulin and antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and [14C]-inulin concentrations were measured by liquid scintillation counting. The marker concentration histories were characterized completely by fully identifiable recirculatory compartmental models. Because neither ICG nor inulin distribute beyond intravascular space before recirculation, their first-pass data were modelled simultaneously to improve confidence in central circulation model parameters. This central circulation model included an estimate of cardiac output that was retained in the recirculatory models of all markers. Three tissue compartments were identified for antipyrine, a lipid soluble marker that equilibrates with tissue (including the lung) and estimates total body water and tissue blood flow. The hydrophilic marker, inulin, diffuses into interstitial fluid so slowly that only two extravascular compartments were identified. These models may be used to determine how cardiac output and its distribution, pulmonary drug uptake, and nondistributive blood flow contribute to variability in patient response to drugs with a rapid onset of effect.

Objective: To devise and test an i.v. methohexital infusion regimen for induction and maintenance of surgical anesthesia in dogs from which they would rapidly recover., Design: Dose-response and plasma concentration-effect study., Animals: 11 clinically normal dogs., Procedure: Bolus methohexital pharmacokinetic variables were determined in ketamine- and pentobarbital-anesthetized dogs. Plasma methohexital concentrations required to inhibit purposeful movement in response to painful stimuli were determined during a stepped methohexital infusion in the same dogs on a second occasion. These pharmacokinetic/pharmacodynamic data were next used to design a bolus and two-stage infusion regimen that would result in stable plasma methohexital concentrations with prolonged infusion. This regimen was tested in a second group of dogs., Results: Mean steady-state volume of distribution of methohexital in the anesthetized dogs was 1.50 L/kg of body weight and mean elimination clearance was 10.2 ml/kg/min. Mean plasma concentrations required to prevent movement response to a noxious stimulus and at which the dogs could be extubated were 11.8 and 6.9 micrograms/ml, respectively. After a 6-hour infusion, recovery of airway reflexes sufficient to allow extubation required 67 minutes., Conclusions: An easily implemented i.v. methohexital infusion regimen for induction and maintenance anesthesia in dogs was developed. During a 6-hour infusion, hemodynamic variables did not change. Use of this regimen resulted in anesthesia of sufficient depth to prevent withdrawal in response to noxious stimuli and in reliable and acceptable emergence times for use in canine survival studies in a cost-effective manner.

We have examined the implications of the theoretical single pharmacokinetic compartment associated with blocker-induced paralysis, in relation to the isolated arm technique. It is assumed that the blocker concentration-effect relationship can be characterized by a sigmoid curve, which incorporates an exponent, s. After tourniquet release, the concentration gradient between the effect compartment and plasma should be large, and elimination related to the rate constant, keo. The major measurement of spontaneous recovery with the isolated arm is the time interval between 75% and 25% twitch depression, T25-T75. The general equation relating these three variables is developed: keo = 2.2/(s x (T25-T75)). Insertion of published values for T25-T75 with isolated arm studies into this equation gave estimates for an intrinsic keo for atracurium, vecuronium, rocuronium and pancuronium.

Background: The rate of administration of an intravenous anesthetic induction agent is an important variable determining the total dose required to reach a given endpoint, such as loss of consciousness (LOC). The influence of infusion rate on the dose-response relationship has not been described rigorously. In this study we characterized the effect of different thiopental infusion rates on the times and doses required to reach a clinical (induction) endpoint., Methods: Fifty-six healthy, non-premedicated men, aged 19-59 yr, were randomly assigned to receive one of seven different thiopental infusion rates (40, 60, 75, 150, 300, 600, and 1,200 mg/min). The infusion was continued until the patient dropped a held object, indicating LOC. The infusion rates were selected using a simulation which predicted the relationship between the rate of administration and cumulative dose administered at the time of LOC. Average population pharmacokinetic parameters from a three-compartment thiopental model were combined with an effect-site rate constant for thiopental equilibration of 0.58 min-1 and a median effect-site concentration of 13.8 mg/l from previously published pharmacokinetic and pharmacodynamic models for thiopental. This derived model was used to predict the total amount of thiopental required, at each infusion rate, to produce LOC., Results: The observed median effective doses for infusion rates of 40-150 mg/min were similar and ranged from 296 to 318 mg. Dose requirements increased significantly with increasing infusion rates greater than 150 mg/min; median effective doses for infusion rates of 300, 600, and 1,200 mg/min were significantly different from each other (436, 555, and 711 mg, respectively). The original simulation underestimated the observed thiopental doses at all but the lowest infusion rate. A new simulation was performed using a recently developed combined pharmacokinetic-pharmacodynamic model. This model incorporated a four-compartment thiopental pharmacokinetic model with quantal dose-response data to derive an effect-site rate constant for thiopental equilibration of 0.29 min-1 and a median effect-site concentration for LOC of 11.3 mg/l. The median thiopental doses predicted by this new simulation under the extreme conditions of a 30-fold range of infusion rates were within 13% of the observed doses., Conclusions: In this study we quantified the relationship between the rate of thiopental administration and the resultant cumulative thiopental dose necessary to produce LOC. This study validated a novel pharmacokinetic-pharmacodynamic model based on a four-compartment pharmacokinetic model and infusion quantal dose-response data. Finally, we demonstrated that thiopental dose-response relationships are dependent on drug administration rate, and found that the ability to predict this dependence accurately is influenced by the pharmacokinetics, pharmacodynamics, and median effect-site concentration used to simulate the dose-response relationships.

A model of antipyrine disposition from the moment of its injection was developed incorporating the intravascular mixing component as determined by indocyanine green (ICG) kinetics. The simultaneous dispositions of antipyrine and ICG were characterized in five dogs anesthetized with halothane. After injecting antipyrine and ICG into the right atrium, femoral arterial blood samples were collected every 3 sec for the 1st min and less frequently to 20 min for ICG and to 360 min for antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and modeled with SAAM 30.1. A fully identifiable recirculatory compartmental model, incorporating the ICG recirculatory model with blood flows and time delays, was used to describe antipyrine disposition. Four distinct antipyrine pharmacokinetic tissue compartments and the distribution clearances assigned to them could be estimated: a pulmonary tissue (0.13 +/- 0.05 I, and 2.51 +/- 0.39 liters/min), a very fast equilibrating tissue (0.12 +/- 0.08 I, and 1.33 +/- 0.22 liters/min), a fast equilibrating tissue (3.21 +/- 0.45 I, and 0.74 +/- 0.09 liters/min) and a slow equilibrating tissue (15.94 +/- 1.8 I, and 0.44 +/- 0.13 liters/min). Although this recirculatory model retains the predominant attributes of traditional pharmacokinetic models, it also can describe completely drug concentrations during the mixing transient when many drugs reach peak effect as well as ascertain the role of cardiac output and its distribution in drug disposition.

The pharmacokinetic-pharmacodynamic model developed here characterizes the relationship between simulated plasma concentrations of thiopental and two dichotomous endpoints determined at induction of anesthesia: loss of voluntary motor power (clinical endpoint), and burst suppression of the electroencephalogram (EEG endpoint). The model incorporated data from two separate thiopental patient studies: a pharmacokinetic study with 21 males, and a pharmacodynamic study with 30 males. In the pharmacodynamic study, cumulative quantal dose-response curves for the clinical and EEG endpoints were developed from observations made during a constant-rate infusion of thiopental. Population mean parameters, derived from the bolus pharmacokinetic thiopental study, were used to simulate concentration-time data for the 150 mg.min-1 thiopental infusion rate used in the dose-response study. A single biophase model incorporating the two endpoints was generated, combining the pharmacokinetic and pharmacodynamic data from the two groups. Estimates of the mean effective thiopental concentrations affecting 50% of the population (EC50S) for the clinical and EEG endpoints were 11.3 and 33.9 micrograms.ml-1, respectively. The half-time for equilibration between arterial thiopental and the effect compartment was 2.6 min. These results are in reasonable agreement with previously described quantal concentration-response data, and with pharmacodynamic models developed for graded EEG responses. Simulation of bolus doses of thiopental with the new model provided ED50s for the clinical and EEG endpoints of 265 mg and 796 mg, respectively; the dose predicted to produce loss of voluntary motor power in 90% of an adult male population was 403 mg. A model combining population pharmacokinetics with cumulative dose-response relationships could prove useful in predicting dosage regimens for those drugs with responses that are categorical.

Dose requirements for thiopental anesthetic induction have significant age- and gender-related variability. We studied the association of the patient characteristics age, gender, weight, lean body mass, and cardiac output with thiopental requirements. Doses of thiopental, infused at 150 mg/min, required to reach both a clinical end-point and an electroencephalographic (EEG) end-point were determined in 30 males and 30 females, aged 18-83 yr. Univariate least squares linear regression analysis revealed outliers in the relationships of age, weight, lean body mass, and cardiac output to thiopental dose at clinical and EEG endpoints. Differential weighting of data points minimized the effect of outliers in the construction of a robust multiple linear regression model of the relationship between several selected independent variables and the dependent variables thiopental dose at clinical and EEG endpoints. The multiple linear regression model for thiopental dose at the clinical end-point selecting the regressor variables age, weight, and gender (R2 = 0.76) was similar to that for age, lean body mass, and gender (R2 = 0.75). Thiopental dose at the EEG endpoint was better described by models selecting the variables age, weight, and cardiac output (R2 = 0.88) or age, lean body mass, and cardiac output (R2 = 0.87). Although cardiac output varied with age, age always remained a selected variable. Because weight and lean body mass differed with gender, their selection as variables in the model eliminated gender as a selected variable or minimized its importance.

The relationship between cardiac output and the tissue distribution of alfentanil was investigated in seven healthy volunteers. Subjects were given 10 micrograms/kg alfentanil and 0.5 mg/kg indocyanine green. Arterial blood samples were obtained at baseline, 1 minute, every 1/2 minute until 5 minutes, and then every minute until 15 minutes after the drug injection was begun. Subsequent samples were collected to 6 hours. Cardiac output was measured continuously by use of thoracic bioimpedance. Alfentanil pharmacokinetics were modeled with both a standard three-compartment model and a four-compartmental model based in part on the two-compartmental pharmacokinetics of indocyanine green. The sum of intercompartmental clearances for both the three- and four-compartment models were significantly correlated with the measured cardiac outputs, r = 0.93 and r = 0.88, respectively. These findings indicate that the intercompartmental clearance (i.e., tissue distribution) of alfentanil is largely determined by cardiac output (i.e., tissue blood flow).

A model of indocyanine green (ICG) disposition from the moment of its injection in blood was developed. ICG disposition was characterized in five dogs deeply anesthetized with halothane, which decreased cardiac output and prolonged intravascular mixing. After ICG injection into the right atrium, femoral arterial blood samples were collected every 3 s for the 1st min and less frequently to 20 min. ICG concentrations were measured by high-performance liquid chromatography and modeled with SAAM 30.1. A fully identifiable recirculatory compartmental model with time delays was used to describe ICG disposition. The central blood volume averaged 23.4 ml/kg, and total blood volume averaged 78.9 ml/kg. Fifty-three percent of the cardiac output flowed through 14% of the peripheral blood volume while the remaining 47% flowed through 86% of the peripheral volume. This new model is isomorphic with a parallel channel, lumped-parameter circulation model and provides more information than stochastic, noncompartmental recirculatory pharmacokinetic techniques. This intravascular mixing model can be applied to determine the contribution of the circulation to drug distribution.

Four cases of cauda equina syndrome occurring after continuous spinal anesthesia are reported. In all four cases, there was evidence of a focal sensory block and, to achieve adequate analgesia, a dose of local anesthetic was given that was greater than that usually administered with a single-injection technique. We postulate that the combination of maldistribution and a relatively high dose of local anesthetic resulted in neurotoxic injury. Suggestions that may reduce the potential for neurotoxicity are discussed. Use of a lower concentration and a "ceiling" or maximum dose of local anesthetic to establish the block should be considered. If maldistribution of local anesthetic is suspected (as indicated by a focal sensory block), the use of maneuvers to increase the spread of local anesthetic is recommended. If such maneuvers prove unsuccessful, the technique should be abandoned.

Certain relationships between dose/concentration and percent response/binding in various biochemical systems are sigmoidal rather than linear. This sigmoid relationship is considered linear only over the 20-80 percent range. Appropriate analysis of such data over nearly the entire response/binding range requires the conversion of the percent response data to probits or probability units, producing a linear relationship. While tables of probits are available, the author has incorporated the probability function for probit conversion into a commercially available spreadsheet program. Also included is the Rohlf and Sokal approximation for the area under the normal distribution curve (conversion of probits to cumulative percent). These functions allow use of a spreadsheet to automate the creation of dose-response curves, or standard curves as part of chemical assays (i.e., radioimmunoassay).

The optimal dose of thiopental depends both on its initial distribution kinetics, which determine its concentrations at sites of action after iv administration, and on its pharmacodynamics. The disposition of concomitantly administered thiopental and indocyanine green (ICG), a marker of intravascular space, was determined in 21 patients, aged 20-80 yr, to determine the pharmacokinetic basis of increased reactivity of the elderly to thiopental. Data obtained from frequent early arterial blood samples and the simultaneous modelling of thiopental disposition with that of ICG allow a rigorous description of early drug distribution. Their disposition is described by a two-compartment ICG model and a four-compartment thiopental model that have a common central volume, V1, the central blood pool. ICG distributes, by intravascular mixing, from V1 to a peripheral blood volume that is a subset of a rapidly equilibrating (fast) peripheral thiopental compartment; elimination clearance of both drugs is modelled from these peripheral compartments. In contrast to the results of others, the results of this study demonstrate that V1 does not decrease with increasing age. The only pharmacokinetic variable that changed with age is the intercompartmental clearance (Cl21) from V1 to the rapidly equilibrating peripheral volume, V2, which decreased 35% between the ages of 20-80 yr. The authors suggest that V1 and the intercompartmental clearances may be used together to explain smaller dose requirements in individuals with increased reactivity to thiopental; such an analysis does not predict that dose adjustments should be made on the basis of age alone.

The kinetics of urea and inulin were analyzed in five anesthetized dogs during sequential 2-hour periods before, during, and after hemodialysis. The distribution of both compounds after simultaneous intravenous injection was characterized by three-compartment models, and the total volumes of urea (0.66 +/- 0.05 L/kg) and inulin (0.19 +/- 0.01 L/kg) distribution were similar to expected values for total body water and extravascular space, respectively. Intercompartmental clearances calculated before dialysis were used to estimate blood flows to the fast and slow equilibrating compartments. In agreement with previous results, the sum of these flows was similar to cardiac output, averaging 101% of cardiac output measured before dialysis (range 72% to 135%). Dialysis was accompanied by reductions in the slow intercompartmental clearances of urea (81%) and inulin (47%), which reflected a 90% attenuation in blood flow supplying the slow equilibrating compartments. This was estimated to result in a 10% average reduction in the efficiency with which urea was removed by dialysis (range 2.0% to 16.4%). Mean arterial pressure fell by less than 5% during dialysis, but total peripheral resistance increased by 47% and cardiac output fell by 35%. In the postdialysis period, total peripheral resistance and cardiac output returned toward predialysis values, but blood flow to the slow equilibrating peripheral compartment was still reduced by 80%. These changes parallel activation of the renin-angiotensin system, but further studies are required to establish causality.

The dispositions of concomitantly administered indocyanine green (ICG) and thiopental were determined in 12 patients undergoing general anesthesia and surgery. These were best characterized by a two-compartment ICG model and a four-compartment thiopental model, chiefly because of data obtained from frequent early arterial blood samples. The models had a common central volume (V1), and the peripheral ICG compartment was the subset of a peripheral thiopental compartment. The two-compartment ICG model described its mixing within the intravascular space. The traditional VC of three-compartment models of thiopental disposition is described by the present four-compartment model as an initial distribution volume, V1, codetermined by ICG as central blood volume, and a rapidly equilibrating peripheral volume, V4. The combined simultaneous ICG-thiopental model more clearly reflects physiology than do the results of earlier curve-fitting techniques and may be useful in studying the pharmacokinetic basis of altered reactivity to thiopental.

The effects of pulmonary artery balloon counterpulsation (PABC) as a circulatory assist for the failing right ventricle were investigated. Sixteen anesthetized dogs underwent instrumentation to measure cardiac output and to record pressures in both ventricles, the pulmonary artery, and the aorta. Autonomic control of the heart was surgically and pharmacologically ablated. A specially designed counterpulsation balloon was inserted through the right ventricular (RV) outflow tract into the pulmonary artery. Pulmonary hypertension, induced acutely by the microembolization of the pulmonary circulation with glass beads combined with infusion of serotonin, served as a model for development of acute RV failure. Immediate effects of PABC were investigated in 10 dogs during normal function and failure of the right ventricle at different levels of preload. After further embolization which caused progressive cardiogenic shock, the effects of 10 minutes of PABC, and of its withdrawal, were examined. In all cases, PABC immediately decreased RV preload and afterload. In the failing right ventricle, counterpulsation also significantly increased cardiac output. Progressive cardiogenic shock was successfully reversed by PABC; after 10 minutes of counterpulsation, increases in cardiac output (+53%), arterial pressure (+55%), and RV minute work (+62%) were observed, paralleled by a fall in RV preload (-22%). After PABC was discontinued, the circulatory status again began to deteriorate. We conclude that PABC effectively improves function of the failing right ventricle caused by acute pulmonary hypertension.

Because alfentanil has been shown to inhibit debrisoquin hydroxylase in vitro, and there is considerable variability in the reported elimination clearance of alfentanil, the possible influence of the debrisoquin metabolic phenotype on the elimination clearance of alfentanil was studied. The disposition of alfentanil was determined after rapid intravenous administration to four extensive debrisoquin metabolizers and three poor debrisoquin metabolizers. Debrisoquin hydroxylation phenotype was determined using the urinary dextromethorphan/dextrorphan metabolic ratio test. The disposition of alfentanil was characterized by a three-compartment open mammillary model. There was no relationship between the dextromethorphan/dextrorphan metabolic ratio and the elimination clearance of alfentanil despite a nearly seven hundred-fold range of the metabolic ratio in the seven volunteers. This indicates that the variability in the elimination clearance of alfentanil is not due to the polymorphism of debrisoquin hydroxylase. Nor is this variability due to variable hepatic blood flow because in this study alfentanil clearance was not related to indocyanine green clearance.

This report describes our experiences with 129 awake oral and nasal fibreoptic intubations in 123 patients considered to be at high risk of aspiration of gastric contents. I.v. sedation was used on all but six occasions. Local anaesthesia was applied to the larynx and trachea through the working channel of the fibrescope on 85 occasions, and by transtracheal injection on 29. Rigid laryngoscopy was necessary after fibreoptic laryngoscopy failed in one patient (with a bleeding peptic ulcer) who vomited a large amount of fresh and clotted blood. No other patient regurgitated during the procedure, and no patient developed evidence of aspiration.