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Positron emission tomography-illuminating in vivo drug disposition
EUROPEAN
European Journal of Pharmaceutical Sciences 2 (1994) 44-46
ELSEVIER
JOURmiAL
OF
PHARMACEUTICAL SCIENCES
Positron emission tomography-illuminating in vivo drug disposition Per Hartvig*, Karl Johan Lindner, Joakim Tedroff, Bengt Lhngstr6m Uppsala Univeristy PET Centre, University Hospital, S-751 85 Uppsala, Sweden
1. Positron emission tomography
Positron emission tomography, PET, is a noninvasive tracer technique which quantitates the kinetics of a radiotracer in a biochemical or physiological process in the tissue of the living animal of the living animal or man. A proper choice of radiotracer enables the quantitation of processes such as blood flow in discrete areas of the brain, tissue pH, blood volume in the tissue and different aspects of energy utilization using radiolabelled oxygen, glucose, acetate or free fatty acids. The quantitation of these process is of fundamental importance in the diagnosis of a number of pathophysiological conditions affecting particularly the brain and heart. Positron emission tomography has become a most powerful tool in clinical oncology, since the utilization of radiolabelled amino acids or glucose not only indicates the localization of tumor, but is also of value for grading of tumor and in the evaluation of treatment effects. Clinical pharmacokinetics heavily rely on the relation of drug effect to plasma concentration of the drug. However, a number of processes obscure this relationship as indicated in Fig. 1. PET
has advantages in these respects in comparison to present methodology. Firstly, PET offers both the possibility of measuring radiolabelled drug concentration in the effect compartment as well as receptor occupancy in studies of the pharmacokinetics of radiolabelled drug. Using compartment models, it is possible to calculate the number of selective binding sites and binding rate constants of the radiolabelled drug. The selectivity of the drug for different types of receptors can also be proved. Similarly, the number of enzyme molecules in the tissue can be quantitated using a radiolabelled enzyme inhibitor. The enzyme activity is quantitated by administration of radiolabelled enzyme substrate. Secondly, pharmacological doses of drug induce physiological effects in the tissue which can be quantitated by PET. Combination of these options increases the understanding of drug kinetics and action. Consequently PET has also found a prominent position in the clinical evaluation of treatment effects of drugs.
2. PET used as an in vivo autoradiographic technique
Dose
4,
Plasma pharmacokinetics
4,
Tissue pharmacokinetics
4,
Drug in effect compartment
4,
0
Receptor occupancy
O
EFFECT
4,
Fig. 1. The relationship between drug dosage and drug effect. * C o r r e s p o n d i n g author. 0928-0987/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved
SSDI 0928-0987(94)00030-4
It was early recognized that PET using radiolabelled drug could improve the understanding of the relation of drug effect to its pharmacokinetics. Pioneering studies with PET showed a displacement of benzodiazepine from specific binding sites in the brain using the benzodiazepine receptor antagonist, flumazenil radiolabelled with 11C (Maziere et al., 1981). The same group also demonstrated that heart rate was directly related to occupancy of cholinergic muscarinic receptors in the myocardium. Opioid drugs such as morphine, codeine and pethidine have been radiolabelled with 11C, and their kinetics in the brain (Hartvig et al., 1984),
P. Hartvig et al. / European Journal of Pharmaceutical Sciences 2 (1994) 44-46
in the spinal canal (Gustafsson et al., 1989) and in the fetus (Lindberg et al., 1985) have been studied with PET. Lipophilicity was a main determinant for uptake and residence time of opioid drugs in the brain as well as their distribution in the spinal canal and to the fetus. It was not possible to localize and quantitate any specific binding of the opioids in the brain. Nevertheless, simple tissue kinetic studies of n c radiolabelled drugs give valuable information compatible with observed differences in clinic effect between opioid drugs. Ketamine is a channel blocker in the NMDAreceptor complex and used clinically as an intravenous anesthetic agent. In low doses ketamine has an analgesic effect but induces also a number of psychotomimetic effects. Plasma concentrations and specific regional binding in the brain measured with PET following a tracer dose and 0.1 and 0.2 mg/kg of (S)-ketamine were related to induced effects such as analgesia, amnesia and other psychotomimetic effects in healthy volunteers (Hartvig et al., 1994). Specific binding in different brain regions was only marginally decreased followed subanesthetic doses of (S)-ketamine. Receptor occupancy was closely related to amnesia and effects such as visual and hearing disturbances and feelings of insobriety and unreality. The ability to withstand ischemic pain, but not sensitivity to heat and cold was also related to specific (S)-ketamine binding in the brain. Studies relating drug effects to concentration at the receptor site would thus give PET a prominent place in pharmacokinetic research. Raclopride is a postsynaptic D2-receptor antagonist which, radiolabelled with 11C, has been used to assess receptor number and antipsychotic drug receptor occupancy in patients with schizophrenia. Although it was not possible to confirm an increased dopamine density in schizophrenic patients (Farde et al., 1987), these studies have had a large impact on the understanding of the mechanism of action and dosage of antipsychotic drugs. The duration of antipsychotic effect was related to dopamine receptor occupancy and not to measured plasma concentrations (Farde et al. 1988). A maximum receptor occupancy was shown even after low doses of antipsychotic drugs (Farde et al., 1989). This information has been a mainstay in a more cautious dosage of antipsychotic drugs. The atypical antipsychotic drug, clozapine, has by means of PET, apart from D2-dopamine receptor binding, been shown to
45
bind to both Dl-dopamine (Nordstr6m, 1993) and to 5HT2-serotonin receptors (Lundberg, to be published 1994).
3. Measurement of drug-induced biochemical response using PET
In clinical oncology PET is routinely used for the assessment of treatment effects (Strauss and Conti, 1991). Non-selective radiotracers quantitating amino acid utilization or glucose consumption in the tumor are used in parallel with selective measures such as radiolabelled receptor ligands or precursor amino acids for quantitation of transmitter synthesis in neuroendocrine tumors. A search for selective radiotracers is considered fundamental for a successful imaging of tumor and treatment effects. Alzheimers disease has no curative treatment. Recently, the choline esterase inhibitor tacrine (tetrahydro-amino acridine) has been shown to be able to postpone development of disease symptoms in the early course of Alzheimers disease. Treatment effects have been investigated with PET using a multitracer protocol with [18F] fluoro-deoxyglucose (FDG) for assessment of glucose brain utilization, nc-butanol for measurement of cerebral blood flow and ( S ) ( - ) - and (R)(+)-[NXlC-methyl]nicotine for quantitation of nicotinic cholinergic receptor function (Nordberg et al., 1992). Tacrine treatment induced an increased (S)(-)[N11C-methyl]nicotine binding in the temporal and frontal cortices compatible with a restoration of nicotinic receptor function. An increased cerebral glucose consumption was also found in mild dementia, but tacrine did not affect cerebral blood flow. The improvements as measured with PET were paralleled by better results in neuropsychological tests. Thus, PET has been shown to be a valuable tool in the quantitation of drug-induced neurochemical changes in the brain. Neurotransmitter synthesis rate of dopamine can be assessed using [/3nC]L-DOPA as tracer (Hartvig et al., 1991). Validation of the method indicated that the decarboxylase activity is quantitated. It has generally been agreed that the decarboxylase enzyme was not influenced by neuronal activity. However, an up-regulation of the synthesis of serotonin in certain aspects of the prefrontal cortex in patients with major depres-
46
P. Hartvig et al. / European Journal of Pharmaceutical Sciences 2 (1994) 44-46
sion ( ~ g r e n et al., 1993) and of dopamine in patients with Parkinson's disease with fluctuating symptoms (Tedroff et al., 1992) has recently been shown. An increased decarboxylase activity can also be obtained after treatment with the co-factor pyridoxine, by 6R-erythro-tetrahydrobiopterin and by simultaneous administration of precursor amino acid. The latter findings give valuable information as to possible drug development for use in diseases characterized by neurotransmitter deficiency as well as a further understanding of the neuronal mechanisms underlying the 'on-off' phenomenon in Parkinson's disease.
4. Conclusions
PET may increase knowledge of both pharmacodynamics and pharmacokinetics in the development of new drugs. Prerequisites for such advantages are a careful validation of methodology and a proper handling of metabolites in compartment models used in the quantitation of tracer kinetics in different physiological processes.
References Agren, H., Reibring, L., Hartvig, P., Tedroff, J. et al. (1993) Monoamine metabolism in human prefrontal cortex and basal ganglia. PET studies using [/3-11C]L-5-hydroxytryptophan and [/3-~IC]L-DOPA in healthy volunteers and patients with unipolar depression. Depression 1, 71-81. Farde, L., Wiesel, F.A., Hall, H., HaRdin, C. et al. (1987) No D2-receptor increase in PET study of schizophrenia. Arch Gen Psychiat 44, 671-672. Farde, L., Wiesel, F.A., Halldin, C. and Sedvall, G. (1988) Central D2-receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiat 43, 71-76.
Farde, L., Eriksson, L., Blomquist, G. and Halldin, C. (1989) Kinetic analysis of central [IiC]raclopride binding to D2-dopamine receptors studied by PET - comparison to equilibrium analysis. J Cerebr Blood Flow Metab 9, 696708. Gustafsson, L.L., Hartvig, P., Bergstr6m, K., Lundqvist, H. et al. (1989) Kinetics of 11C-labelled morphine and pethidine after epidural and intrathecal administration in the Rhesus monkey. Acta Anesthesiol Scand 33, 105-111. Hartvig, P., Bergstr6m, K, Lindberg, B., Lundberg, P.O. et al. (1984) Kinetics of nC-labeled opiates in the brain of Rhesus monkey. J Pharmacol Exp Ther 230, 250-255. Hartvig, P., Agren, H., Reibring, L., Tedroff, J. et al. (1991) Brain kinetics of L-[/3-nC]DOPA in humans studied by positron emission tomography. J Neural Transm 86, 25-41. Hartvig, P., Valtysson, J., Lindner, K.J., Kristenssen, J. et al. (1994) Pharmacodynamic relationships of subanesthetic doses of (S)-ketamine to plasma and brain concentrations measured with positron emission tomography. Clin Pharmacol Therap. submitted. Lindberg, B.S., Berglund, L., Hartvig, P., Lindgren, P.G. et al. (1985) Positron emission tomography in experimental perinatology. J Perinat med 13, 277-286. Mazi6re, M., Godot, J.M., Berger, G., Baron, J.C. et al. (1981) Positron emission tomograph: a new method for in vivo brain studies of benzodiazepine receptors. In: E. Costa (Ed.) GABA and Benzodiazepine Receptors. Raven Press, New York, o19. 273-285. Nordberg, A., Lilja, A., Lundqvist, H., Hartvig, P. et al. (1992) Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimers patients visualized by positron emission tomography. Neurobiol Ageing 13,747758. Nordstr6m, A.L. (1993) Doctoral thesis, Karolinska Institute, Stockholm. Strauss, L.G. and Conti, P.S. (1991) The application of PET in clinical oncology. J Nucl Med 32, 623-645. Tedroff, J., Aquilonius, S.M., Hartvig, P., Bredberg, E. et al. (1992) Cerebral uptake and utilization of (~1C) LDOPA in Parkinson's disease measured by positron emission tomography: relation to motor response. Acta Neurol Scand 85, 95-102.
European Journal of Pharmaceutical Sciences 2 (1994) 44-46
ELSEVIER
JOURmiAL
OF
PHARMACEUTICAL SCIENCES
Positron emission tomography-illuminating in vivo drug disposition Per Hartvig*, Karl Johan Lindner, Joakim Tedroff, Bengt Lhngstr6m Uppsala Univeristy PET Centre, University Hospital, S-751 85 Uppsala, Sweden
1. Positron emission tomography
Positron emission tomography, PET, is a noninvasive tracer technique which quantitates the kinetics of a radiotracer in a biochemical or physiological process in the tissue of the living animal of the living animal or man. A proper choice of radiotracer enables the quantitation of processes such as blood flow in discrete areas of the brain, tissue pH, blood volume in the tissue and different aspects of energy utilization using radiolabelled oxygen, glucose, acetate or free fatty acids. The quantitation of these process is of fundamental importance in the diagnosis of a number of pathophysiological conditions affecting particularly the brain and heart. Positron emission tomography has become a most powerful tool in clinical oncology, since the utilization of radiolabelled amino acids or glucose not only indicates the localization of tumor, but is also of value for grading of tumor and in the evaluation of treatment effects. Clinical pharmacokinetics heavily rely on the relation of drug effect to plasma concentration of the drug. However, a number of processes obscure this relationship as indicated in Fig. 1. PET
has advantages in these respects in comparison to present methodology. Firstly, PET offers both the possibility of measuring radiolabelled drug concentration in the effect compartment as well as receptor occupancy in studies of the pharmacokinetics of radiolabelled drug. Using compartment models, it is possible to calculate the number of selective binding sites and binding rate constants of the radiolabelled drug. The selectivity of the drug for different types of receptors can also be proved. Similarly, the number of enzyme molecules in the tissue can be quantitated using a radiolabelled enzyme inhibitor. The enzyme activity is quantitated by administration of radiolabelled enzyme substrate. Secondly, pharmacological doses of drug induce physiological effects in the tissue which can be quantitated by PET. Combination of these options increases the understanding of drug kinetics and action. Consequently PET has also found a prominent position in the clinical evaluation of treatment effects of drugs.
2. PET used as an in vivo autoradiographic technique
Dose
4,
Plasma pharmacokinetics
4,
Tissue pharmacokinetics
4,
Drug in effect compartment
4,
0
Receptor occupancy
O
EFFECT
4,
Fig. 1. The relationship between drug dosage and drug effect. * C o r r e s p o n d i n g author. 0928-0987/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved
SSDI 0928-0987(94)00030-4
It was early recognized that PET using radiolabelled drug could improve the understanding of the relation of drug effect to its pharmacokinetics. Pioneering studies with PET showed a displacement of benzodiazepine from specific binding sites in the brain using the benzodiazepine receptor antagonist, flumazenil radiolabelled with 11C (Maziere et al., 1981). The same group also demonstrated that heart rate was directly related to occupancy of cholinergic muscarinic receptors in the myocardium. Opioid drugs such as morphine, codeine and pethidine have been radiolabelled with 11C, and their kinetics in the brain (Hartvig et al., 1984),
P. Hartvig et al. / European Journal of Pharmaceutical Sciences 2 (1994) 44-46
in the spinal canal (Gustafsson et al., 1989) and in the fetus (Lindberg et al., 1985) have been studied with PET. Lipophilicity was a main determinant for uptake and residence time of opioid drugs in the brain as well as their distribution in the spinal canal and to the fetus. It was not possible to localize and quantitate any specific binding of the opioids in the brain. Nevertheless, simple tissue kinetic studies of n c radiolabelled drugs give valuable information compatible with observed differences in clinic effect between opioid drugs. Ketamine is a channel blocker in the NMDAreceptor complex and used clinically as an intravenous anesthetic agent. In low doses ketamine has an analgesic effect but induces also a number of psychotomimetic effects. Plasma concentrations and specific regional binding in the brain measured with PET following a tracer dose and 0.1 and 0.2 mg/kg of (S)-ketamine were related to induced effects such as analgesia, amnesia and other psychotomimetic effects in healthy volunteers (Hartvig et al., 1994). Specific binding in different brain regions was only marginally decreased followed subanesthetic doses of (S)-ketamine. Receptor occupancy was closely related to amnesia and effects such as visual and hearing disturbances and feelings of insobriety and unreality. The ability to withstand ischemic pain, but not sensitivity to heat and cold was also related to specific (S)-ketamine binding in the brain. Studies relating drug effects to concentration at the receptor site would thus give PET a prominent place in pharmacokinetic research. Raclopride is a postsynaptic D2-receptor antagonist which, radiolabelled with 11C, has been used to assess receptor number and antipsychotic drug receptor occupancy in patients with schizophrenia. Although it was not possible to confirm an increased dopamine density in schizophrenic patients (Farde et al., 1987), these studies have had a large impact on the understanding of the mechanism of action and dosage of antipsychotic drugs. The duration of antipsychotic effect was related to dopamine receptor occupancy and not to measured plasma concentrations (Farde et al. 1988). A maximum receptor occupancy was shown even after low doses of antipsychotic drugs (Farde et al., 1989). This information has been a mainstay in a more cautious dosage of antipsychotic drugs. The atypical antipsychotic drug, clozapine, has by means of PET, apart from D2-dopamine receptor binding, been shown to
45
bind to both Dl-dopamine (Nordstr6m, 1993) and to 5HT2-serotonin receptors (Lundberg, to be published 1994).
3. Measurement of drug-induced biochemical response using PET
In clinical oncology PET is routinely used for the assessment of treatment effects (Strauss and Conti, 1991). Non-selective radiotracers quantitating amino acid utilization or glucose consumption in the tumor are used in parallel with selective measures such as radiolabelled receptor ligands or precursor amino acids for quantitation of transmitter synthesis in neuroendocrine tumors. A search for selective radiotracers is considered fundamental for a successful imaging of tumor and treatment effects. Alzheimers disease has no curative treatment. Recently, the choline esterase inhibitor tacrine (tetrahydro-amino acridine) has been shown to be able to postpone development of disease symptoms in the early course of Alzheimers disease. Treatment effects have been investigated with PET using a multitracer protocol with [18F] fluoro-deoxyglucose (FDG) for assessment of glucose brain utilization, nc-butanol for measurement of cerebral blood flow and ( S ) ( - ) - and (R)(+)-[NXlC-methyl]nicotine for quantitation of nicotinic cholinergic receptor function (Nordberg et al., 1992). Tacrine treatment induced an increased (S)(-)[N11C-methyl]nicotine binding in the temporal and frontal cortices compatible with a restoration of nicotinic receptor function. An increased cerebral glucose consumption was also found in mild dementia, but tacrine did not affect cerebral blood flow. The improvements as measured with PET were paralleled by better results in neuropsychological tests. Thus, PET has been shown to be a valuable tool in the quantitation of drug-induced neurochemical changes in the brain. Neurotransmitter synthesis rate of dopamine can be assessed using [/3nC]L-DOPA as tracer (Hartvig et al., 1991). Validation of the method indicated that the decarboxylase activity is quantitated. It has generally been agreed that the decarboxylase enzyme was not influenced by neuronal activity. However, an up-regulation of the synthesis of serotonin in certain aspects of the prefrontal cortex in patients with major depres-
46
P. Hartvig et al. / European Journal of Pharmaceutical Sciences 2 (1994) 44-46
sion ( ~ g r e n et al., 1993) and of dopamine in patients with Parkinson's disease with fluctuating symptoms (Tedroff et al., 1992) has recently been shown. An increased decarboxylase activity can also be obtained after treatment with the co-factor pyridoxine, by 6R-erythro-tetrahydrobiopterin and by simultaneous administration of precursor amino acid. The latter findings give valuable information as to possible drug development for use in diseases characterized by neurotransmitter deficiency as well as a further understanding of the neuronal mechanisms underlying the 'on-off' phenomenon in Parkinson's disease.
4. Conclusions
PET may increase knowledge of both pharmacodynamics and pharmacokinetics in the development of new drugs. Prerequisites for such advantages are a careful validation of methodology and a proper handling of metabolites in compartment models used in the quantitation of tracer kinetics in different physiological processes.
References Agren, H., Reibring, L., Hartvig, P., Tedroff, J. et al. (1993) Monoamine metabolism in human prefrontal cortex and basal ganglia. PET studies using [/3-11C]L-5-hydroxytryptophan and [/3-~IC]L-DOPA in healthy volunteers and patients with unipolar depression. Depression 1, 71-81. Farde, L., Wiesel, F.A., Hall, H., HaRdin, C. et al. (1987) No D2-receptor increase in PET study of schizophrenia. Arch Gen Psychiat 44, 671-672. Farde, L., Wiesel, F.A., Halldin, C. and Sedvall, G. (1988) Central D2-receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiat 43, 71-76.
Farde, L., Eriksson, L., Blomquist, G. and Halldin, C. (1989) Kinetic analysis of central [IiC]raclopride binding to D2-dopamine receptors studied by PET - comparison to equilibrium analysis. J Cerebr Blood Flow Metab 9, 696708. Gustafsson, L.L., Hartvig, P., Bergstr6m, K., Lundqvist, H. et al. (1989) Kinetics of 11C-labelled morphine and pethidine after epidural and intrathecal administration in the Rhesus monkey. Acta Anesthesiol Scand 33, 105-111. Hartvig, P., Bergstr6m, K, Lindberg, B., Lundberg, P.O. et al. (1984) Kinetics of nC-labeled opiates in the brain of Rhesus monkey. J Pharmacol Exp Ther 230, 250-255. Hartvig, P., Agren, H., Reibring, L., Tedroff, J. et al. (1991) Brain kinetics of L-[/3-nC]DOPA in humans studied by positron emission tomography. J Neural Transm 86, 25-41. Hartvig, P., Valtysson, J., Lindner, K.J., Kristenssen, J. et al. (1994) Pharmacodynamic relationships of subanesthetic doses of (S)-ketamine to plasma and brain concentrations measured with positron emission tomography. Clin Pharmacol Therap. submitted. Lindberg, B.S., Berglund, L., Hartvig, P., Lindgren, P.G. et al. (1985) Positron emission tomography in experimental perinatology. J Perinat med 13, 277-286. Mazi6re, M., Godot, J.M., Berger, G., Baron, J.C. et al. (1981) Positron emission tomograph: a new method for in vivo brain studies of benzodiazepine receptors. In: E. Costa (Ed.) GABA and Benzodiazepine Receptors. Raven Press, New York, o19. 273-285. Nordberg, A., Lilja, A., Lundqvist, H., Hartvig, P. et al. (1992) Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimers patients visualized by positron emission tomography. Neurobiol Ageing 13,747758. Nordstr6m, A.L. (1993) Doctoral thesis, Karolinska Institute, Stockholm. Strauss, L.G. and Conti, P.S. (1991) The application of PET in clinical oncology. J Nucl Med 32, 623-645. Tedroff, J., Aquilonius, S.M., Hartvig, P., Bredberg, E. et al. (1992) Cerebral uptake and utilization of (~1C) LDOPA in Parkinson's disease measured by positron emission tomography: relation to motor response. Acta Neurol Scand 85, 95-102.