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Sökning: hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Medicinska och farmaceutiska grundvetenskaper) hsv:(Farmaceutiska vetenskaper) > (2000-2009) > (2006) > Hammarlund Udenaes Margareta

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1.
  • Boström, Emma, et al. (författare)
  • In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat : Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics
  • 2006
  • Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 34:9, s. 1624-1631
  • Tidskriftsartikel (refereegranskat)abstract
    • The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.
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2.
  • Espefält Westin, Ulrika, et al. (författare)
  • Direct nose-to-brain transfer of morphine after nasal administration to rats
  • 2006
  • Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 23:3, s. 565-572
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: The aim of this study was to quantify the olfactory transfer of morphine to the brain hemispheres by comparing brain tissue and plasma morphine levels after nasal administration with those after intravenous administration. METHODS: Morphine (1.0 mg/kg body weight) was administered via the right nostril or intravenously as a 15-min constant-rate infusion to male rats. The content of morphine and its metabolite morphine-3-glucuronide in samples of the olfactory bulbs, brain hemispheres, and plasma was assessed using high-performance liquid chromatography, and the areas under the concentration-time curves (AUC) were calculated. RESULTS: At both 5 and 15 min after administration, brain hemisphere morphine concentrations after nasal administration were similar to those after i.v. administration of the same dose, despite lower plasma concentrations after nasal administration. The brain hemispheres/plasma morphine AUC ratios for the 0-5 min period were thus approximately 3 and 0.1 after nasal and i.v. administration, respectively, demonstrating a statistically significant early distribution advantage of morphine to the brain hemispheres via the nasal route. CONCLUSION: Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.
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3.
  • Gupta, Anubha, et al. (författare)
  • Brain distribution of cetirizine enantiomers : comparison of three different tissue-to-plasma partition coefficients : K(p), K(p,u), and K(p,uu)
  • 2006
  • Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 34:2, s. 318-323
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this study was to compare the blood-brain barrier (BBB) transport and brain distribution of levo- (R-CZE) and dextrocetirizine (S-CZE). Microdialysis probes, calibrated using retrodialysis by drug, were placed into the frontal cortex and right jugular vein of eight guinea pigs. Racemic CZE (2.7 mg/kg) was administered as a 60-min i.v. infusion. Unbound and total concentrations of the enantiomers were measured in blood and brain with liquid chromatography-tandem mass spectrometry. The brain distribution of the CZE enantiomers were compared using the parameters K(p,) K(p,u,) K(p,uu), and V(u,br). K(p) compares total brain concentration to total plasma concentration, K(p,u) compensates for binding in plasma, whereas K(p,uu) also compensates for binding within the brain tissue and directly quantifies the transport across the BBB. V(u,br) describes binding within the brain. The stereoselective brain distribution indicated by the K(p) of 0.22 and 0.04 for S- and R-CZE, respectively, was caused by different binding to plasma proteins. The transport of the CZE enantiomers across the BBB was not stereoselective, since the K(p,uu) was 0.17 and 0.14 (N.S.) for S- and R-CZE, respectively. The K(p,uu) values show that the enantiomers are effluxed to a large extent across the BBB. The V(u,br) of approximately 2.5 ml/g brain was also similar for both the enantiomers, and the value indicates high binding to brain tissue. Thus, when determining stereoselectivity in brain distribution, it is important to study all factors governing this distribution, binding in blood and brain, and the BBB equilibrium.
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4.
  • Gupta, Anubha, 1974- (författare)
  • Role of the Blood-Brain Barrier in Stereoselective Distribution and Delay in H1 Receptor Occupancy of Cetirizine in the Guinea Pig Brain
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Cetirizine, an H1-antihistamine, is prescribed for allergic disorders. It exists as a racemic mixture, with levocetirizine being the active enantiomer. The central nervous system side-effects of H1-antihistamines are caused by their penetration into the brain. In this thesis the plasma pharmacokinetics, transport across the blood-brain barrier (BBB) and H1 receptor occupancy of cetirizine enantiomers was investigated in vivo in guinea pigs. The transport across the BBB was quantified using the microdialysis technique. Stereoselective brain distribution was investigated by measuring both unbound and total concentrations in plasma and brain. The time aspects of the H1 receptor occupancy of levocetirizine was studied in the brain and the periphery.The plasma pharmacokinetics of cetirizine was stereoselective with clearance and volume of distribution of levocetirizine being approximately half that of dextrocetirizine. This was mainly due to the differences in plasma protein binding of the enantiomers. The stereoselectivity in brain distribution indicated by the partition coefficient Kp (total AUC ratio brain to plasma) was caused by stereoselective plasma protein binding. The transport across the BBB measured in this thesis by the unbound partition coefficient Kp,uu (unbound AUC ratio brain to plasma) was the same for the two enantiomers. Binding within the brain was also not significantly different. The H1 receptor occupancy of levocetirizine in brain lagged behind the plasma concentrations whereas it was not delayed with respect to the brain concentrations. This indicates that the delayed brain H1 receptor occupancy of levocetirizine is caused by a slow transport across the BBB.In summary, the results of this thesis emphasize the importance of measuring both the unbound and total concentrations in blood and brain to characterize stereoselective brain distribution. The thesis also emphasize the importance of taking local brain pharmacokinetics into consideration in understanding pharmacokinetic-pharmacodynamic relationships of drugs with central activity.
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5.
  • Gupta, Anubha, et al. (författare)
  • Stereoselective pharmacokinetics of cetirizine in the guinea pig : Role of protein binding
  • 2006
  • Ingår i: Biopharmaceutics & drug disposition. - : Wiley. - 0142-2782 .- 1099-081X. ; 27:6, s. 291-297
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose. To characterize the pharmacokinetics of cetirizine enantiomers in the guinea pig including protein binding in both the guinea pig and human plasma. Methods. Plasma concentrations of cetirizine enantiomers in the guinea pig were determined using a LC-MS/MS method after a short i.v. infusion (1, 2 and 4 mg/kg) of racemic cetirizine. Protein binding was determined using an in vitro equilibrium dialysis technique. A pharmacokinetic model was developed using NONMEM and the differences in pharmacokinetic parameters of levocetirizine and dextrocetirizine were estimated. Results. The plasma concentration time data of both the enantiomers were best described by a three-compartment pharmacokinetics model. The clearance (CL) of levocetirizine and dextrocetirizine was 1.2 and 2.7 ml/min, respectively, and the volume of distribution at steady state (V-ss) was 457 ml and 996 ml, respectively. The fraction unbound (f(u)) in guinea pig plasma for levocetirizine and dextrocetirizine was 7-10% and 16-21% while in human plasma, it was 8% and 12%, respectively. The factor describing the difference in the pharmacokinetic parameters of the cetirizine enantiomers was estimated to be 2.26. Conclusions. Cetirizine pharmacokinetics is stereoselective in the guinea pig. For levocetirizine, CL and V-ss were half those of dextrocetirizine, indicating that protein binding is an important factor affecting the pharmacokinetics of cetirizine. The effect of protein binding on the pharmacokinetics of the cetirizine enantiomers could be extrapolated to humans.
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6.
  • Lundquist, Pinelopi, et al. (författare)
  • Validation studies on the 5-hydroxy-L-[beta-11C]-tryptophan/PET method for probing the decarboxylase step in serotonin synthesis
  • 2006
  • Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 59:8, s. 521-531
  • Tidskriftsartikel (refereegranskat)abstract
    • The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.
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7.
  • Syvänen, Stina, et al. (författare)
  • Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET
  • 2006
  • Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 32:3, s. 1134-1141
  • Tidskriftsartikel (refereegranskat)abstract
    • Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.
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8.
  • Syvänen, Stina, et al. (författare)
  • Pharmacokinetic consequences of active drug efflux at the blood-brain barrier
  • 2006
  • Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 23:4, s. 705-717
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations. METHODS: Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin. RESULTS: The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K(p,uu). CONCLUSIONS: Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.
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9.
  • Syvänen, Stina, et al. (författare)
  • Predicting brain concentrations of drug using positron emission tomography and venous input : modeling of arterial-venous concentration differences
  • 2006
  • Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 62:10, s. 839-848
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVEIn a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T(av)).METHODSBrain kinetics (C(br)) was described as the convolution of arterial plasma kinetics (C(ar)) with an arterial-to-brain impulse response function (T(br)). The arterial plasma kinetics was obtained as venous plasma kinetics (C(ve)) convolved with the inverse of the arterio-venous transform (T(av) (-1)). The brain kinetics was then given by C(br)=C(ve)*T(av) (-1)*T(br). This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.RESULTSThe venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.CONCLUSIONWe demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.
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