paroxetine, Paxil
Potent depletion of 5HT from monkey whole blood by a new 5HT uptake inhibitor, paroxetine (FG 7051).

Petersen EN, Bechgaard E, Sortwell RJ, Wetterberg L.

The potent 5-hydroxytryptamine (5HT) uptake inhibitor FG 7051 (paroxetine, INN) was administered to rhesus monkeys in doses of 1.0, 2.5 or 7.5 mg/kg by oral gavage once daily for 13 weeks. Blood samples for analysis of 5HT in whole blood and paroxetine in plasma were taken prior to and after 1, 4 and 13 weeks of treatment. The lowest dose 1 mg/kg caused 30% depletion of 5HT in whole blood with a level of paroxetine in plasma below 2 ng/ml. Doses of 2.5 mg/kg produced an 85% depletion of 5HT and a steady state plasma concentration of about 5 ng paroxetine/ml, while 7.5 mg/kg caused a 93% depletion of 5HT and a steady state plasma concentration of 100--450 ng paroxetine/ml. There was no concentration-dependent 5HT reduction with the highest dose level suggesting that maximal depletion was produced by concentrations below 100 ng/ml. The results showed that paroxetine is a strong depletor of 5HT from whole blood of monkeys conceivably because it inhibits 5HT uptake inhibition. The effect of the drug reached its maximum within 1 week and no tolerance developed during 13 weeks.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=102515&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Binding potency of paroxetine analogues for the 5-hydroxytryptamine uptake complex.

Mathis CA, Gerdes JM, Enas JD, Whitney JM, Taylor SE, Zhang Y, McKenna DJ, Havlik S, Peroutka SJ.

Research Medicine and Radiation Biophysics Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

The in-vitro inhibition constants (Ki) of 14 structural analogues of the potent 5-hydroxytryptamine (5-HT)-uptake inhibitor paroxetine were determined to assess the structure-affinity relationship of these derivatives. A goal of these studies was to determine those positions on paroxetine which could be derivatized without significantly decreasing the affinity of the drug for the binding site, so that radiolabels such as [18F]fluoroalkyl groups might be appended for future in-vivo imaging studies of the 5-HT uptake system. Using the methyl moiety as a steric probe for these studies, it was found that the rank order of potency of various methyl-substituted paroxetine analogues for inhibiting the binding of [3H]paroxetine to the 5-HT re-uptake site was: 4'-approximately equal to 3'-approximately equal to 2''- > 2'-approximately equal to 1- > 5''- > 6''-methyl. The in-vitro equipotent molar ratios (EPMR, Ki(analogue)/Ki(paroxetine)) of the analogues were determined, and the EPMRs of the 4'-, 3'-, and 2''-methyl derivatives were 1.9, 2.2 and 2.2, respectively. The 4'- and 2''-fluoromethyl and -fluoroethyl analogues were synthesized, and the EPMRs of the 4'- and 2''-fluoromethyl derivatives were determined to be 2.0 and 3.5, and those of the 4'- and 2''-fluoroethyl analogues were 5.2 and 6.2, respectively. The 2''-fluoromethyl analogue was unstable in aqueous solutions, and it is not a promising ligand for in-vivo studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1360504&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
[3H]paroxetine binding and serotonin content of rat cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region following p-chlorophenylalanine and p-chloroamphetamine treatment.

Dewar KM, Grondin L, Carli M, Lima L, Reader TA.

Hopital Louis-H. Lafontaine, Departement de Psychiatrie, Montreal, Quebec, Canada.

The agents p-chlorophenylalanine (PCPA) and p-chloroamphetamine (PCA) deplete brain serotonin (5-HT) levels by two different mechanisms; PCPA inhibits the enzyme tryptophan hydroxylase, whereas PCA has a neurotoxic action on certain 5-HT neurons. The parameters of [3H]paroxetine binding to homogenates prepared from the cerebral cortex of rats treated with PCPA, PCA, or saline; vehicle were investigated. The tissue concentrations of 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) were also determined by HPLC in the same brain samples. After PCPA treatment, neither the maximum binding capacity (Bmax) nor the dissociation constant (KD) of [3H]paroxetine for the 5-HT uptake recognition site differed from controls despite a substantial reduction in the concentration of 5-HT and 5-HIAA. In contrast, significant changes in both the Bmax and KD values were observed in the cerebral cortex of rats treated with PCA. Furthermore, [3H]paroxetine binding and tissue concentrations of 5-HT and 5-HIAA were measured in the following different regions of the rat brain: cingulate, parietal, and visual cortical areas; dorsal and ventral hippocampus; rostral and caudal halves of neostriatum; ventral mesencephalic tegmentum; and midbrain raphe nuclei region after administration of PCPA, PCA, or saline vehicle. There was an excellent correlation between regional 5-HT levels and specific [3H]paroxetine binding in control and PCA-treated rats although this correlation was lost after PCPA treatment. Under these conditions, the 5-HT innervation remains unchanged whereas the concentration of 5-HT and 5-HIAA is greatly reduced. Thus, [3H]paroxetine binding appears to provide a reliable marker of 5-HT innervation density within the mammalian CNS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1370077&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.

Bloomer JC, Woods FR, Haddock RE, Lennard MS, Tucker GT.

Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, Welwyn, Hertfordshire.

Paroxetine is a selective serotonin reuptake inhibitor possessing anti-depressant activity. Demethylenation of the methylenedioxy phenyl group is the initial step in its metabolism, the liberated carbon appearing in vitro as formate. A radioassay involving [14C-methylenedioxy] paroxetine was developed and used to examine the role of cytochrome P4502D6 in paroxetine metabolism by human liver microsomes. The rate of formate production was much higher in microsomes from an extensive metaboliser of debrisoquine than from a poor metaboliser. Also, demethylenation of paroxetine was inhibited by the quinidine and quinine isomer pair in microsomes from the extensive metaboliser only. These observations strongly suggested that the process was catalysed by the enzyme cytochrome P4502D6. Metabolism could not be completely inhibited by quinidine, the residual activity representing the contribution of at least one other enzyme. The ability of microsomes from a poor metaboliser of debrisoquine to demethylenate paroxetine provided further evidence for the involvement of an enzyme distinct from P4502D6. This was confirmed by kinetic analysis of the process in microsomes from both poor and extensive metabolisers. It is concluded that, in man, the initial step of paroxetine metabolism is performed by at least two enzymes, one of which is cytochrome P4502D6.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1388041&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Inhibition of [3H]paroxetine binding by various serotonin uptake inhibitors: structure-activity relationships.

Marcusson JO, Norinder U, Hogberg T, Ross SB.

Department of Geriatric Medicine, University of Linkoping, Sweden.

Fifty-four compounds structurally related to zimeldine or alaproclate and eight reference substances were examined as inhibitors of the high affinity binding of [3H]paroxetine to rat cerebral cortical membranes as a measure of the affinity of the 5-hydroxytryptamine (5-HT) transporter. None of the compounds had an affinity as high as paroxetine (KD = 0.026 nM). The most potent compound, 3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine (2) had a 5 times lower affinity than paroxetine. Some other diphenyl-1-methyl-propylamines displayed high affinity, e.g. the 4-bromo (4) and 2-bromo (7) derivatives. The primary amine analogue of zimeldine substituted with an alpha-methyl group (19) had an affinity only slightly less than that of norzimeldine (11) but an almost 100 times higher affinity than that of the unsubstituted primary zimeldine analogue (57). These observations indicate that a methyl group on the alpha-carbon and on the nitrogen both increase the affinity for the [3H]paroxetine binding site. The structure activity relationship for the compounds to inhibit [3H]paroxetine binding was highly significantly correlated to the inhibition of 5-HT uptake in mouse brain slices (P less than 0.01) and to the inhibition of noradrenaline uptake in the same slices (P less than 0.05). QSAR analysis of the zimeldine series of compounds indicates that substitution of halogens of the 2-position of the phenyl ring is unfavourable. The cis configuration promotes higher activity than the trans configuration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1396986&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Sodium dependence of [3H]paroxetine binding and 5-[3H]hydroxytryptamine uptake in rat diencephalon.

Mann CD, Hrdina PD.

Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ontario, Canada.

The sodium dependence of binding of [3H]-paroxetine, a selective serotonin uptake inhibitor, to the serotonin transporter in rat diencephalon was studied in both brain membranes and tissue sections and compared with that of 5-[3H]hydroxytryptamine ([3H]5-HT) uptake by synaptosomes from the same region. Binding of [3H]-paroxetine in both the membranes and sections displayed clear sodium dependence until a plateau occurring at 60 nM NaCl, the EC50 for sodium being 8 and 25 mM, respectively. The affinity (1/KD) of [3H]paroxetine binding was a simple hyperbolic function of sodium concentration. In contrast, the density of [3H]paroxetine sites was not affected by external Na+ concentration. The uptake of [3H]5-HT showed a similar pattern of sodium dependence with an EC50 for Na+ of 25 mM. Both the affinity (1/Km) and the rate (Vmax) of [3H]5-HT uptake were dependent on external [Na+] with sodium-dependence curves fitting a rectangular hyperbola. The kinetic analysis of results indicates that one sodium ion is required for the binding of [3H]paroxetine as well as for the binding and translocation of each [3H]5-HT molecule. The results concur with a single-site model of the sodium-dependent serotonin transporter with common or overlapping domains for 5-HT and 5-HT uptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1402927&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Quantitative autoradiography of 3H-paroxetine binding sites in rat brain.

Chen HT, Clark M, Goldman D.

Laboratory on Clinical Studies, NIAAA, Bethesda, Maryland.

The use of 3H-paroxetine as a ligand for quantitative autoradiography of serotonin (5-HT) transport sites was optimized, and the distribution of 3H-paroxetine binding sites in rat brain was studied. Under the conditions described, 3H-paroxetine binding in forebrain sections was of high affinity and saturable, with a Kd of 0.18 +/- 0.02 nM (mean +/- SEM) and Bmax of 268 +/- 12 fmol/mg of protein (n = 3). Nonspecific binding was 10.7% +/- 1.0 of the total binding (n = 8). The distribution of 3H-paroxetine binding sites closely matched the regional distribution of 5-HT nerve terminals and cell bodies. The highest concentrations of 3H-paroxetine binding sites were found in the dorsal raphe nucleus (563 +/- 55 fmol/mg tissue, n = 4), and high densities of binding were also found in the locus coeruleus, medial forebrain bundle, substantia nigra, several limbic structures (amygdala, hippocampus, hypothalamus, olfactory tubercle, septum, and thalamus), and components of the visual relay system (superior colliculus and the lateral geniculate body). Although lesioning of 5-HT neurons with p-chloroamphetamine (PCA) drastically eliminated 3H-paroxetine binding in most regions of the rat brain, significant binding remained in the raphe nuclei and medial forebrain bundle suggesting that 3H-paroxetine binding in these regions was to presynaptic sites on cell bodies or axons relatively resistant to PCA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1421530&dopt=Abstract paroxetine, Paxil, Paxil CR