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The metabolism and excretion of “amphetamines” in man
lvüi
Frontiers in Catecholamine Reaeorch
To evaluate the possible contributions of activity differences to these data, a group of ten moderately depressed patients were asked to simulate the hyperactivity of mania for four hours preceding a lumbar puncture . The following changes were noted : Baseline (Mod . Dep.) HVA
16 .9 t 2 .8
MHPG
7.5 t 2 .2
Activity 42 .1 t 5.7 14 .2
f
3.4
(p = < .Ol)
(p -_ < 0.1)
Although these data suggest a possible activity artifact in CSF catecholamine metabolite data, we were not able to demonstrate any relationship between èIHPG levels and ratings of agitation-retardation in the depressed patients ; there was a trend for HVA levels to be higher in the less retarded and more agitated in depressed patients .
Conclusions : Our data, as well as additional data to be reviewed, suggests that unipolar and bipolar affective illness may represent biologically distinct entities with different clinical responses to drugs effecting brain catecholamines . In regard to bipolar affective illness we would suggest a broadening of biological theories to include both an underlying dysfunction and a superimposed dysfunction . The underlying dysfunction (which may not directly involve catecholamines is present in both the depressive and magic phases and probably involves a genetic component constituting the biological predisposition to both manic and depressive episodes . The existence of as underlying dysfunction common to both phases of bipolar affective illness is consistent with the acute and prophylactic effects of lithium in both the manic and depressive phases of bipolar illness. Our pharmacological data would support the concept that the superimposed dysfunction involved in the `switch" into mania involves alteration in brain catecholamines . The level of psychomotor activation may be the aspect of bipolar affective illness most clearly related to catecholamine function, varying in an increase-decrease fashion with functional changes in central catecholamine systems. THE METABOLISM AND EXCRETION OF 'AMPHETAMINES" IN MAN ] . w. Gorrod
Department of Pharmacy, Chelsea College (University of Logdon), Manresa Road, S .W .3 A wide variety of drugs based oo amphetamine ~ß-phenylisopropylamine) I
Frontiers in Catecholamine Research
lix
are used in clinical practice for a diverse range of conditions
These drugs contain groups substituted either in the aromatic ring, in the isopropyl side chain or on the amino group; such substituents considerably alter the physical chemical characteristics of the molecule which in turn alter the pharmacokinetic excretion profiles of the drug. The parent amine is capable of oxidation in the ring, on the side chain or undergoing deamiaation, the metabolic routes preferred being influenced by the nature of the substituents . `AmphetaminesA being basic substances with pK a values in the range 8 -10 are sensitive to urinary pH changes which control the amount of unionised drug available and hence kidney reabsorbtion . Only under conditions of controlled acidic urinary pH can meaningful urinary kinetic data be obtained . Amphetamine metabolism in man has been studied by several groups of workers, whilst exact comparison is not possible due to lack of urinary pH control, certain trends emerge as a constant pattern. The amount of unchanged amphetamine excreted in the urine varies enormously from less than 1096 under alkaline conditions to over 6096 under acidic urinary conditions . The maj or route of metabolism of amphetamine in man is via deamiaation; this route, which ultimately leads to the formation of conj agates of benzoic acid, occurs to about 20g6 of the dose administered . Hydroxylation in the 4 position of the molecule is a minor route of metabolism of amphetamine in man rarely exceeding 596 of the dose . /3-hydroxylation of amphetamine end its metabolite 4-hydroxy amphetamine to produce norephedrine and 4hydroxynorephedrine has also been reported as a minor route of metabolism in man. Molecular modification by substitution of the amino group with alkyl or aralkyl moieties generally have three effects (a) they lead to a lower total urinary recovery of the unchanged drug and metabolite (dealkylated product),
lx
Fr~tiers in Catecholamine Hesearch (b) they alter the amount of amphetamine metabolically produced, (c) they alter the stereo selectivity of the amounts of unchanged drug recovered. The degree of effect observed depends on the nature of the substituent.
Similarly, substitution in the aromatic ring generally leads to far greater metabolism occurring and hence lower urinary excretion of the unchanged drug; in the case of 4-hydroxyamphetamine, however, the presence of a group capable of direct conj ugation, without oxidative metabolic modification allows excretion of high levels of the drug . The data presented will be discussed in relation to the mechanism of formation of metabolites and metabonates found in biological systems. AMINERGIC RECEPTORS IN NEURAL TISSUE : DOPAMIIVE-, OCTOPAMINE- AND SEROTONIN-SENSITIVE ADENYLATE CYCLASES Paul Greengard, John W. Kebabian and James A. Nathanson Department of Pharmacology, Yale University School of Medicine New Haven, Connecticut 08b10, U.S .A Studies have been carried out on several relatively simple neuronal preparations in an effort to elucidate the cellular basis for the physiological actions of various amines . Our evidence is compatible with the possibility that, at various loci within both vertebrate and invertebrate nervous systems, the actions of certain amines are mediated through stimulation of the activity of adenylate cyclase in the postsynaptic membranes. In the rabbit superior cervical ganglion, preganglionic stimulation causes a several-fold increase in cyclic AMP levels . A variety of biochemical and physiological evidence supports the contention that this increase is mediated by dopamine, released from interneurons, activating a dopamine-sensitive adenylate cyclase present is the postganglionic neurons. A dopamine~ensitive adenylate cyclase has also been identified within the rat caudate nucleus. The stimulation by dopamine of the caudate adenylate cyclase activity displays many of the pharmacological properties of the dopamine receptor which has been indirectly studied by other investigators. In the insect thoracic nerve ganglion, three distinct amine receptors for adenylate cyclase have been identified . In addition to a dopamine-sensitive adenylate cyclase, this simple neural preparation contains distinct octopamine-
Frontiers in Catecholamine Reaeorch
To evaluate the possible contributions of activity differences to these data, a group of ten moderately depressed patients were asked to simulate the hyperactivity of mania for four hours preceding a lumbar puncture . The following changes were noted : Baseline (Mod . Dep.) HVA
16 .9 t 2 .8
MHPG
7.5 t 2 .2
Activity 42 .1 t 5.7 14 .2
f
3.4
(p = < .Ol)
(p -_ < 0.1)
Although these data suggest a possible activity artifact in CSF catecholamine metabolite data, we were not able to demonstrate any relationship between èIHPG levels and ratings of agitation-retardation in the depressed patients ; there was a trend for HVA levels to be higher in the less retarded and more agitated in depressed patients .
Conclusions : Our data, as well as additional data to be reviewed, suggests that unipolar and bipolar affective illness may represent biologically distinct entities with different clinical responses to drugs effecting brain catecholamines . In regard to bipolar affective illness we would suggest a broadening of biological theories to include both an underlying dysfunction and a superimposed dysfunction . The underlying dysfunction (which may not directly involve catecholamines is present in both the depressive and magic phases and probably involves a genetic component constituting the biological predisposition to both manic and depressive episodes . The existence of as underlying dysfunction common to both phases of bipolar affective illness is consistent with the acute and prophylactic effects of lithium in both the manic and depressive phases of bipolar illness. Our pharmacological data would support the concept that the superimposed dysfunction involved in the `switch" into mania involves alteration in brain catecholamines . The level of psychomotor activation may be the aspect of bipolar affective illness most clearly related to catecholamine function, varying in an increase-decrease fashion with functional changes in central catecholamine systems. THE METABOLISM AND EXCRETION OF 'AMPHETAMINES" IN MAN ] . w. Gorrod
Department of Pharmacy, Chelsea College (University of Logdon), Manresa Road, S .W .3 A wide variety of drugs based oo amphetamine ~ß-phenylisopropylamine) I
Frontiers in Catecholamine Research
lix
are used in clinical practice for a diverse range of conditions
These drugs contain groups substituted either in the aromatic ring, in the isopropyl side chain or on the amino group; such substituents considerably alter the physical chemical characteristics of the molecule which in turn alter the pharmacokinetic excretion profiles of the drug. The parent amine is capable of oxidation in the ring, on the side chain or undergoing deamiaation, the metabolic routes preferred being influenced by the nature of the substituents . `AmphetaminesA being basic substances with pK a values in the range 8 -10 are sensitive to urinary pH changes which control the amount of unionised drug available and hence kidney reabsorbtion . Only under conditions of controlled acidic urinary pH can meaningful urinary kinetic data be obtained . Amphetamine metabolism in man has been studied by several groups of workers, whilst exact comparison is not possible due to lack of urinary pH control, certain trends emerge as a constant pattern. The amount of unchanged amphetamine excreted in the urine varies enormously from less than 1096 under alkaline conditions to over 6096 under acidic urinary conditions . The maj or route of metabolism of amphetamine in man is via deamiaation; this route, which ultimately leads to the formation of conj agates of benzoic acid, occurs to about 20g6 of the dose administered . Hydroxylation in the 4 position of the molecule is a minor route of metabolism of amphetamine in man rarely exceeding 596 of the dose . /3-hydroxylation of amphetamine end its metabolite 4-hydroxy amphetamine to produce norephedrine and 4hydroxynorephedrine has also been reported as a minor route of metabolism in man. Molecular modification by substitution of the amino group with alkyl or aralkyl moieties generally have three effects (a) they lead to a lower total urinary recovery of the unchanged drug and metabolite (dealkylated product),
lx
Fr~tiers in Catecholamine Hesearch (b) they alter the amount of amphetamine metabolically produced, (c) they alter the stereo selectivity of the amounts of unchanged drug recovered. The degree of effect observed depends on the nature of the substituent.
Similarly, substitution in the aromatic ring generally leads to far greater metabolism occurring and hence lower urinary excretion of the unchanged drug; in the case of 4-hydroxyamphetamine, however, the presence of a group capable of direct conj ugation, without oxidative metabolic modification allows excretion of high levels of the drug . The data presented will be discussed in relation to the mechanism of formation of metabolites and metabonates found in biological systems. AMINERGIC RECEPTORS IN NEURAL TISSUE : DOPAMIIVE-, OCTOPAMINE- AND SEROTONIN-SENSITIVE ADENYLATE CYCLASES Paul Greengard, John W. Kebabian and James A. Nathanson Department of Pharmacology, Yale University School of Medicine New Haven, Connecticut 08b10, U.S .A Studies have been carried out on several relatively simple neuronal preparations in an effort to elucidate the cellular basis for the physiological actions of various amines . Our evidence is compatible with the possibility that, at various loci within both vertebrate and invertebrate nervous systems, the actions of certain amines are mediated through stimulation of the activity of adenylate cyclase in the postsynaptic membranes. In the rabbit superior cervical ganglion, preganglionic stimulation causes a several-fold increase in cyclic AMP levels . A variety of biochemical and physiological evidence supports the contention that this increase is mediated by dopamine, released from interneurons, activating a dopamine-sensitive adenylate cyclase present is the postganglionic neurons. A dopamine~ensitive adenylate cyclase has also been identified within the rat caudate nucleus. The stimulation by dopamine of the caudate adenylate cyclase activity displays many of the pharmacological properties of the dopamine receptor which has been indirectly studied by other investigators. In the insect thoracic nerve ganglion, three distinct amine receptors for adenylate cyclase have been identified . In addition to a dopamine-sensitive adenylate cyclase, this simple neural preparation contains distinct octopamine-