Cerebral Kinetics Research Articles

Excess cerebral oxygen delivery follows return of spontaneous circulation in near-term asphyxiated lambs

Hypoxic-ischaemia renders the neonatal brain susceptible to early secondary injury from oxidative stress and impaired autoregulation. We aimed to describe cerebral oxygen kinetics and haemodynamics immediately following return of spontaneous circulation (ROSC) and evaluate non-invasive parameters to facilitate bedside monitoring. Near-term sheep fetuses [139 ± 2 (SD) days gestation, n = 16] were instrumented to measure carotid artery (CA) flow, pressure, right brachial arterial and jugular venous saturation (SaO2 and SvO2, respectively). Cerebral oxygenation (crSO2) was measured using near-infrared spectroscopy (NIRS). Following induction of severe asphyxia, lambs received cardiopulmonary resuscitation using 100% oxygen until ROSC, with oxygen subsequently weaned according to saturation nomograms as per current guidelines. We found that oxygen consumption did not rise following ROSC, but oxygen delivery was markedly elevated until 15 min after ROSC. CrSO2 and heart rate each correlated with oxygen delivery. SaO2 remained > 90% and was less useful for identifying trends in oxygen delivery. CrSO2 correlated inversely with cerebral fractional oxygen extraction. In conclusion, ROSC from perinatal asphyxia is characterised by excess oxygen delivery that is driven by rapid increases in cerebrovascular pressure, flow, and oxygen saturation, and may be monitored non-invasively. Further work to describe and limit injury mediated by oxygen toxicity following ROSC is warranted.

Influence of binding affinity and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of two novel xanthine PET radioligands for the A1 adenosine receptor

IntroductionThe suitability of novel positron emission tomography (PET) radioligands for quantitative in vivo imaging is affected by various physicochemical and pharmacological parameters. In this study, the combined effect of binding affinity, lipophilicity, protein binding and blood plasma level on cerebral pharmacokinetics and PET imaging characteristics of three xanthine-derived A1 adenosine receptor (A1AR) radioligands was investigated in rats. MethodsA comparative evaluation of two novel cyclobutyl-substituted xanthine derivatives, 8-cyclobutyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CBX) and 3-(3-[18F]fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine ([18F]MCBX), with the reference A1AR radioligand 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) was conducted. This evaluation included in vitro competition binding assays, in vitro autoradiography and in vivo PET imaging. Differences in cerebral pharmacokinetics and minimal scan duration required for quantification of cerebral distribution volume (VT) were assessed. ResultsMeasured Ki values of non-labeled CBX, MCBX and CPFPX were 10.0 ± 0.52 nM, 3.3 ± 0.30 nM and 1.4 ± 0.15 nM, respectively (n = 3–4). In vitro autoradiographic binding patterns in rat brain were comparable between the radioligands, as well as the fraction of non-specific binding (1.0–1.9%). In vivo cerebral pharmacokinetics of the novel cyclobutyl-substituted xanthines differed considerably from that of [18F]CPFPX. Brain uptake and VT of [18F]CBX were substantially lower despite the higher concentration of radiotracer in plasma. [18F]MCBX showed comparable uptake and VT, but faster cerebral kinetics than [18F]CPFPX. However, the faster kinetics of [18F]MCBX did not enable the quantification of cerebral VT in a shorter scan time. ConclusionsThe combined effect of individual physicochemical and pharmacological properties of a radiotracer on its PET imaging characteristics cannot be readily predicted. In vivo performance of the xanthine A1AR radioligands was mainly influenced by binding affinity; plasma concentrations and cerebral kinetics were of secondary importance.

Influence of high ambient temperatures on the physiological responses and body sway in healthy young adults after quickly standing.

This study was aimed to compare the variations in cerebral oxygenation, blood pressure and center-of-foot pressure after standing from sitting and supine positions at normal (22 degrees C) and high (32 degrees C) room temperatures. Thirty young adults stood up from a resting posture (sitting or supine position) and kept the static standing posture for 90 sec. Meanwhile, their center-of-foot pressure (COP), blood pressure, and cerebral oxygenation kinetics were measured in continuity. The change of the frequency domain low-to-high frequency (LF/HF) ratio of the R-R interval before and after standing from a supine position was significantly higher than that from a sitting position under both temperature conditions. Blood pressure as well as total and oxygenated hemoglobin levels decreased immediately after standing up and the ratio of blood pressure change when moving from a supine position to standing at high room temperature was the largest as compared with the other conditions. Total hemoglobin (Hb) volume was found to temporarily decrease after standing and required 22-24 sec to recover when the subject started from the sitting position and 33-36 sec when the subject started from the supine position. Cerebral oxygenation kinetics tended to be larger under high, rather than normal, temperature conditions. All COP parameters after standing were significantly larger in the high temperature condition than in the normal temperature condition. Body sway after standing was larger in the high temperature condition than in the normal temperature condition and after standing from a supine position than from a sitting position. In conclusion, cerebral oxygenation kinetics and blood pressure measured after the subject moved to the standing position changed dramatically under high temperature conditions, and variations in this parameter may influence body sway.

Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil

(R)-[(11)C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[(11)C]verapamil is the fact that its main metabolite, [(11)C]D617, also enters the brain. For quantitative analysis of (R)-[(11)C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[(11)C]verapamil and [(11)C]D617 are indeed similar and, if so, whether [(11)C]D617 itself could serve as an alternative PET tracer for P-gp. [(11)C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [(11)C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg·kg(-1), intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15mg·kg(-1), intravenously), as well as metabolite analysis (n=4). The precursor for the radiosynthesis of [(11)C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [(11)C]D617 was synthesized in 58%-77% decay-corrected yield with a radiochemical purity of ≥99%. The homogeneously distributed cerebral volume of distribution (V(T)) of [(11)C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment. V(T) of [(11)C]D617 was comparable to that of (R)-[(11)C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[(11)C]verapamil and [(11)C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.

Evaluation of Cerebral Acetate Transport and Metabolic Rates in the Rat Brain in vivo Using 1H-[13C]-NMR

Acetate is a well-known astrocyte-specific substrate that has been used extensively to probe astrocytic function in vitro and in vivo. Analysis of amino acid turnover curves from (13)C-acetate has been limited mainly for estimation of first-order rate constants from exponential fitting or calculation of relative rates from steady-state (13)C enrichments. In this study, we used (1)H-[(13)C]-Nuclear Magnetic Resonance spectroscopy with intravenous infusion of [2-(13)C]acetate-Na(+) in vivo to measure the cerebral kinetics of acetate transport and utilization in anesthetized rats. Kinetics were assessed using a two-compartment (neuron/astrocyte) analysis of the (13)C turnover curves of glutamate-C4 and glutamine-C4 from [2-(13)C]acetate-Na(+), brain acetate levels, and the dependence of steady-state glutamine-C4 enrichment on blood acetate levels. The steady-state enrichment of glutamine-C4 increased with blood acetate concentration until 90% of plateau for plasma acetate of 4 to 5 mmol/L. Analysis assuming reversible, symmetric Michaelis-Menten kinetics for transport yielded 27+/-2 mmol/L and 1.3+/-0.3 micromol/g/min for K(t) and T(max), respectively, and for utilization, 0.17+/-0.24 mmol/L and 0.14+/-0.02 micromol/g/min for K(M_util) and V(max_util), respectively. The distribution space for acetate was only 0.32+/-0.12 mL/g, indicative of a large excluded volume. The astrocytic and neuronal tricarboxylic acid cycle fluxes were 0.37+/-0.03 micromol/g/min and 1.41+/-0.11 micromol/g/min, respectively; astrocytes thus comprised approximately 21%+/-3% of total oxidative metabolism.

Comparison of intravenous and intraperitoneal [123I]IBZM injection for dopamine D2 receptor imaging in mice

Intraperitoneal (IP) injection represents an attractive alternative route of radiotracer administration for small animal imaging, e.g., for longitudinal studies in transgenic mouse models. We explored the cerebral kinetics of the reversible dopamine D2 receptor ligand [(123)I]IBZM after IP injection in mice. Cerebral [(123)I]IBZM kinetics were assessed by ex vivo autoradiography in mice sacrificed between 30 and 200 min after IP or intravenous (IV) injection. The striatum-to-cerebellum (S/C) uptake ratio at 140 min was evaluated in wild-type mice and R6/2 transgenic mice (a Huntington's disease model) in comparison with in vitro autoradiography using [(3)H]raclopride. [(123)I]IBZM uptake was slower and lower after IP injection [maximum uptake in striatum 5.6% injected dose per gram (ID/g) at 60 min] than IV injection (10.5%ID/g at 30 min). Between 60 and 120 min, striatal (cerebellar) uptake after IP injection reached 63% (91%) of the uptake after IV injection. The S/C uptake ratio increased to 15.5 at 200 min after IP injection, which corresponds to 87% of the IV injection value (17.8). Consistent with in vitro [(3)H]raclopride autoradiography, the S/C ratio given by ex vivo [(123)I]IBZM autoradiography (140 min after IP injection) was significantly reduced in R6/2 mice. Although IP injection resulted in slower kinetics, relevant measures of dopamine D2 receptor availability were comparable. Thus, IP injection represents a promising route of tracer administration for small animal [(123)I]IBZM SPECT. This should considerably simplify the implementation of longitudinal small animal neuroimaging studies, e.g., in transgenic mouse models.

PHARMACOKINETICS AND PHARMACODYNAMICS OF INDOMETHACIN: EFFECTS ON CEREBRAL BLOOD FLOW IN ANAESTHETIZED SHEEP

1. Indomethacin has been used to manage raised intracranial pressure (ICP) in humans during neuroanaesthesia and neurosurgery. Indomethacin causes cerebral vasoconstriction and reduces cerebral blood flow (CBF) and, therefore, ICP. 2. The systemic kinetics, cerebral kinetics and cerebral dynamics of indomethacin (0.2 mg/kg) were measured and modelled using a population approach. Data were collected using an instrumented sheep preparation with raised ICP and under either isoflurane or propofol anaesthesia to parallel the clinical use of indomethacin in neurosurgery. 3. The systemic kinetics of indomethacin could be described by a two-compartment model, with small distribution volumes and a clearance of 0.68 L/min. The cerebral kinetics of indomethacin could be described using a model with a cerebral distribution volume between 5 and 8 mL and a loss term of 3.3 mL/min, the latter probably representing slow diffusion across the blood-brain barrier. 4. The changes in CBF lagged behind the blood concentrations of indomethacin. Indirect response models with turnover times of 1.70-4.08 min were generally better able to describe the effect of indomethacin on CBF than effect compartment models. 5. There was a non-linear concentration-effect relationship, with the maximum possible reduction in CBF being to 73-74% of baseline. 6. The data and model support the concept of indomethacin having limited uptake into the brain, with its effect on CBF being the result of its action on the endothelium, where it indirectly modifies the turnover of a compound regulating vascular tone.

CEREBRAL UPTAKE OF DRUGS IN HUMANS

1. Drugs that target the central nervous system (CNS) are under-represented in the pharmacopoeia because of the difficulties of overcoming passive and active defences of the blood-brain barrier (BBB). Methods have been developed in drug discovery to make decisions about whether a compound crosses the BBB. Less is known about how the rate and extent of CNS penetration of a drug affects its clinical behaviour, largely because of past difficulties in measuring the cerebral uptake of drugs in humans. Three methods for doing so are reviewed. 2. Microdialysis is sometimes used as a clinical tool for monitoring the brain in neurointensive care and opportunistic pharmacological studies are possible. The method is relatively cheap and simple, measures free drug concentrations and is better suited to characterizing slowly changing brain drug concentrations. 3. Measuring cerebral drug uptake using positron emission tomography imaging requires the use of short-lived isotopes (labelled drug or labelled receptor ligand). Data with high spatial and temporal resolution can be collected, but the method requires expensive infrastructure. 4. Jugular bulb catheters collect pure brain venous blood and are sometimes placed for neuromonitoring. Cerebral drug uptake is inferred from the arterial to cerebral venous concentration difference. The method is relatively cheap and simple and allows global brain concentrations to be estimated. It is better suited to characterizing rapidly changing brain concentrations and effects. 5. The cerebral kinetics of a cerebro-active drug can make substantial contributions to its clinical behaviour. For example, loperamide is a peripherally acting opioid that has little CNS effect due to the active efflux transport of loperamide from the brain back into the blood by transporters including P-glycoprotein. The opioids alfentanil and fentanyl differ in their duration of action largely because of differences in their cerebral distribution volume rather than differences in systemic kinetics. The onset of anaesthesia of the intravenous anaesthetic propofol is governed almost completely by the kinetics of the first-pass passage of the drug through the brain and is more affected by changes in cerebral blood flow than hepatic clearance. 6. Continuing to exploit and develop these methods may provide new avenues to enhance the safety and efficacy of cerebro-active drugs in clinical practice.

Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model

The pharmacokinetics and time course of blood–brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg−1 BUP or 0.6 mg kg−1 norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min−1) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min−1) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood–brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 ± 0.08 and 1.18 ± 0.04 (mean ± SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

Pharmacogenetics of Opioids

Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics and dosage requirements. Single-nucleotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Sertürner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.

Blood–brain distribution of morphine‐6‐glucuronide in sheep

At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep. Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements. A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2. Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.

Blood–brain equilibration kinetics of levo‐α‐acetyl‐methadol using a chronically instrumented sheep preparation

1.--The delayed onset and long duration of action of the opioid agonist levo-alpha-acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood-brain equilibration of LAAM itself. 2.--The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0-75 min) were measured using a validated HPLC assay. 3.--LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. 4.--Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood-brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min(-1)) and a large cerebral distribution volume (724 ml). 5.--In conclusion, pharmacokinetic-pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.

The Acute Disposition of (R)- and (S)-Methadone in Brain and Lung of Sheep

The cerebral and lung kinetics of the enantiomers of methadone were quantified using a conscious chronically instrumented sheep preparation, as these organs are the major organs governing the peak brain concentrations (and therefore effects) of methadone after ivbolus administration. Seven sheep were administered intravenous infusions of rac-methadone (30 mg over 4 min). Whole blood (R)- and (S)-methadone concentrations were measured using stereoselective HPLC. Methadone transiently increased cardiac output (CO) and mean arterial pressure, but did not alter cerebral blood flow (CBF) or cause significant respiratory depression. Using physiologically based kinetic models, cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and CBF, lung kinetics from pulmonary artery-aortic gradient and CO. Lung and cerebral kinetics were best described by a partially membrane-limited model for both enantiomers. Lung kinetics displayed clear stereoselectivity, due to the smaller apparent volume of the deep lung compartment for (R)-methadone (45 l) compared to (S)-methadone (79 l). This resulted in systemic differences in the concentrations of the enantiomers. Minimal stereoselectivity was observed in cerebral kinetics. The brain:blood equilibration of methadone was slow (half-life of 18 min) due to intermediate permeability and large apparent cerebral distribution volumes. However, the permeability term was sufficiently high that cerebral kinetics were affected by CBF. Simulations demonstrated that if CBF was doubled, the equilibration half-life of methadone with brain tissue decreased by 30%, and there was a 25% increase in the peak brain concentrations. Future studies are needed to confirm the role of cerebral blood flow alterations in the exposure of the brain to methadone, especially in the case of respiratory depression. In conclusion, pharmacokinetic modelling of methadone confirmed a large equilibration delay between brain and blood.

Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats

Benzodiazepine poisoning causes coma and respiratory depression. Our objective was to determine whether, and to what extent, arterial blood gas disturbances correlated with blood or cerebral kinetics of midazolam. A 160 mg kg −1 single dose of midazolam was infused intravenously over 20 min in catheterized male Sprague–Dawley rats. Midazolam kinetics was simultaneously determined in plasma and brain using striatal microdialysis. Midazolam concentrations were measured using a high-performance liquid chromatographic assay with ultraviolet detection. Midazolam (160 mg kg −1) reproducibly induced deep coma with respiratory acidosis. Plasma midazolam kinetics was well described by a bi-exponential model, with an elimination half-life of 6.4 ± 1.8 h. The striatal dialysate concentration peaked at 50.0 ± 8.9 min after the end of infusion, with a significant delay to peak concentration compared to plasma. Respiratory depression, assessed by the elevation in PaCO 2, was more closely correlated with midazolam striatal dialysate rather than plasma kinetics. These results suggest a central mechanism for midazolam respiratory effects at toxic doses in rats. In conclusion, our study showed a delayed onset in peak PaCO 2 and pH effects after the slow infusion of a toxic dose of midazolam in rats. The effects on arterial blood gases were better correlated with midazolam striatal concentrations than with plasma concentrations. This study may contribute to better understanding of benzodiazepine-induced respiratory depression in poisonings.

Recirculatory model of fentanyl disposition with the brain as the target organ

The factors affecting the concentrations of fentanyl in the brain after intravenous administration have not been completely quantified. A model integrating the role of brain, lung and systemic kinetics was developed based on data from conscious instrumented sheep. Brain kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. The best models of the lung and brain were incorporated into a recirculatory model of the whole-body disposition of fentanyl. The validity of the model structure was tested by its ability to describe published data on the effect of hypo-, normo- and hypercarbia on the blood and brain concentrations of fentanyl in anaesthetized dogs. The cerebral kinetics of fentanyl were consistent with partial membrane limitation: the time to 50% equilibration with arterial blood was 10.0 min. Lung kinetics had two distinct components: a shallow compartment that was 50% equilibrated with blood in 0.72 min, and a loss term probably representing sequestration. Despite its simplicity, the recirculatory model was an adequate description of the sheep data. The dog data could be described if cerebral blood flow and cardiac output in the model were allowed to differ between hypo-, normo- and hypercarbic states. The required flow changes were in good agreement with the known effect of these states in the dog. A recirculatory model with the brain as a target organ defined the quantitative relationship between the brain concentrations of fentanyl and the circulatory state.

Cerebral and lung kinetics of morphine in conscious sheep after short intravenous infusions

The analgesic effects of morphine are delayed relative to its concentration in blood. The rate of equilibration of morphine between blood and brain may contribute to this delay, but the kinetics of this process have not been modelled. This was determined in conscious instrumented sheep. The lung kinetics of morphine were also determined given their importance in defining systemic kinetics after i.v. bolus administration. Sheep were given short i.v. infusions of morphine (30 mg over 4 min). Cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. These data were fitted to flow- and membrane-limited models of the kinetics in each organ. Morphine had minimal cardiovascular effects, did not alter cerebral blood flow and caused insignificant respiratory depression. Lung kinetics were best described by a single distribution volume (2036 ml) with a first-order loss (1370 ml min(-1)), which was attributed to deep distribution. The cerebral kinetics of morphine were characterized by a significant permeability barrier. Permeability across the barrier (7.44 ml min(-1)) was estimated with good precision, and was approximately one-fifth of the nominal cerebral blood flow. The distribution volume of morphine in the brain was estimated with less precision, but was described by a brain:blood partition coefficient of approximately 1.4. The time required for 50% equilibration between brain and blood concentrations was approximately 10.3 min. The cerebral equilibration of morphine was relatively slow, and was characterized by significant membrane limitation.

Theoretical Aspects of P-glycoprotein Mediated Drug Efflux on the Distribution Volume of Anaesthetic-related Drugs in the Brain

P-glycoprotein in the membranes of endothelial cells actively transports some drugs out of the brain. The theoretical effect of P-glycoprotein mediated drug efflux on the cerebral distribution volumes of drugs was examined, with particular emphasis on anaesthetic-related drugs (often characterized by moderate to high permeability across the blood brain barrier due to their lipophilicity and intermediate molecular weight). An analytical equation for the cerebral distribution volume in the presence of the efflux was derived, and validated by modelling the same system using differential equations. The efflux was shown to lower both the membrane and intracellular drug concentrations in parallel, and to reduce the time required for brain:blood equilibration. The net effect of the efflux was governed by the ratio of the P-glycoprotein drug clearance from the membrane (Pcl) and the permeability of the membrane (PS). It was therefore a balance between the rate that a drug could be pumped out of the membrane by the efflux system, and the rate that the drug leaked back in due to the permeability of the membrane for the drug. The effect of the efflux was therefore more pronounced for drugs with membrane-limited cerebral kinetics (e.g. morphine), but was nevertheless significant for drugs with more flow-limited kinetics (e.g fentanyl). The cerebral distribution volume was also influenced by the free fraction in blood and the free fraction in the intracellular space in the conventional manner. There are no theoretical limitations to the P-glycoprotein system influencing the cerebral distribution volume of moderately lipophilic anaesthetic-related drugs.

The cerebral and systemic kinetics of thiopentone and propofol in halothane anaesthetized sheep.

The cerebral and systemic kinetics of intravenous thiopentone (250 mg over 2 minutes, n=5) and propofol (100 mg over 2 minutes, n=6) were determined in sheep anaesthetized with halothane (2.0%) and mechanically ventilated to an end-expired carbon dioxide tension of 40 mmHg. The sheep were previously instrumented with arterial and sagittal sinus (effluent from the brain) blood sampling catheters. Systemic kinetics were inferred from the time-course of the arterial blood concentrations, and cerebral kinetics from the time-course of the arterio-sagittal sinus concentration difference across the brain. Under halothane anaesthesia, the peak arterial concentrations of each drug occurred at the end of the two-minute infusion, and was 42.3 mg/l and 12.3 mg/l for thiopentone and propofol, respectively. Propofol had a significantly larger systemic clearance (3.19 l/min) than thiopentone (0.99 l/min). The brain concentrations of propofol equilibrated more slowly with the arterial concentrations than those of thiopentone. The extraction ratio across the brain near the end of the infusions (1.5 min) were 0.85 and 0.46 respectively. These data were also compared to analogous previously published data for initially conscious sheep. The systemic kinetics of thiopentone were little affected by halothane anaesthesia. For propofol, halothane anaesthesia was associated with a statistically significant reduction in clearance (50% of awake), a slower initial half-life (247% of awake), and the emergence of a second slower half-life in some sheep. The cerebral kinetics of both drugs were subtly altered by halothane anaesthesia.

The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep.

Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption. The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data. The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion. The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.

In vivo PET study of cerebral [11C] methyl- tetrahydroaminoacridine distribution and kinetics in healthy human subjects.

It is unclear whether the palliative effects of tetrahydroaminoacridine (THA) (tacrine, Cognex) on the clinical symptoms of patients affected by Alzheimer's disease (AD) are the result of its inhibitory activity on acetylcholinesterase or on other complex sites of action. In order to investigate the cerebral distribution and kinetics of THA in the human brain in vivo, we performed positron emission tomography (PET) imaging with [11C]N-methyl-tetrahydro-aminoacridine (MTHA) in healthy human volunteers. After intravenous injection, [11C]MTHA crossed the blood-brain barrier and reached its maximum uptake between 10 and 40 minutes, depending on the brain regions. Uptake was higher in the grey matter structures, and lower in the white matter. After this peak, the radioactivity remained quasi- constant until 60 minutes in all regions with a half-life varying from 2.44 hours in the thalamus to 3.42 hours in the cerebral cortex. The ratios of regional to whole cerebral cortex brain radioactivity calculated between 50 and 70 minutes after the tracer injection were 1.14 +/- 0.04, 1.07 +/- 0. 03 and 1.06 +/- 0.04 in the putamen, cerebellum and thalamus, respectively. Overall, these results show that: (1) [11C]MTHA crosses the blood-brain barrier easily and is highly concentrated in the brain; (2) the regional brain distribution of [11C]MTHA does not parallel that of in vivo acetylcholinesterase (AChE) concentrations; and (3) the cerebral kinetics of [11C]MTHA are consistent with known plasmatic pharmacokinetics of THA in AD patients. We conclude that PET imaging with [11C]MTHA is a useful method for assessing the cerebral distribution and kinetics of THA in vivo.