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PubMed1995

Differential symptom reduction in depressed cocaine abusers treated with psychotherapy and pharmacotherapy.

We evaluated treatment response for depressed versus nondepressed ambulatory cocaine abusers in a 12-week randomized controlled trial of desipramine and cognitive-behavioral treatment, alone and in combination. Subjects with depressive symptomatology at baseline tended to have better retention and better cocaine outcomes compared with nondepressed subjects. Desipramine was an effective antidepressant in this sample and was associated with significantly greater reduction in depressive symptoms than was placebo; however, desipramine treatment was not associated with greater reductions in cocaine use for either the depressed or euthymic subgroup. Cognitive-behavioral relapse prevention treatment was associated with significantly longer periods of consecutive abstinence and better retention compared with supportive clinical management for the depressed subgroup, but psychotherapy condition did not have an effect on depressive symptoms. These data point to differential symptom reduction in depressed cocaine addicts and underscore the importance of evaluating combined psychotherapy-pharmacotherapy approaches for this population.

Adult↗
PubMedDate not supplied

Pre- and postsynaptic effects of SKF64139, a phenylethanolamine N-methyltransferase inhibitor, in conscious normotensive rats.

We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.

Animals↗
PubMed1990

Nonlinear kinetics of imipramine in low and medium plasma level ranges.

Steady state plasma concentrations of imipramine and desipramine were studied at three to nine different imipramine dose levels in 17 extensive metabolizers of sparteine and at two dose levels in two poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. The imipramine doses were changed stepwise from doses yielding plasma concentrations of imipramine plus desipramine below 150 nM, up to doses yielding therapeutic drug levels of at least 300-500 nM. The imipramine doses required to achieve therapeutic drug levels was 20 or 25 mg/day in the two poor metabolizers and 50-350 mg/day in the extensive metabolizers. In the extensive metabolizers, the concentration/dose ratio increased for imipramine and desipramine with increasing dose. Dose adjustments based on a simple linear prediction from drug levels at initial dose (50 or 75 mg imipramine/day) thus would result in 0-130% (median, 20%) overestimates, most pronounced in patients with initial low steady state levels. The nonlinear kinetics of imipramine thus may be a significant clinical problem in patients treated for diabetic neuropathy symptoms.

Adult↗
PubMed2000

Prejunctional muscarinic receptor modulation of noradrenaline release from sympathetic neurones in rabbit aorta.

The prejunctional muscarinic modulation of stimulation-evoked release of 3H-noradrenaline from sympathetic neurones in rabbit aorta was examined. The role of transmitter uptake, alpha-adrenoceptor blockade, stimulation frequency and endothelium on the modulation was investigated. Rings of aorta were incubated with (-)-3H-noradrenaline and subsequently subjected to electrical-field stimulation. Fractional 3H-overflow was determined by liquid scintillation counting. Acetylcholine (10(-8)-3 x 10(-6) M) added cumulatively, reduced the stimulation-evoked 3H-overflow up to 80%. The effect of acetylcholine was the same in intact and endothelium-free aorta. The inhibitory effect of acetylcholine was inversely related to the frequency of stimulation (1-10 Hz). The maximal inhibition (%) was 80 (1 Hz), 53 (3 Hz) and 14 (10 Hz). The inhibitory effect of acetylcholine (10(-6) M) and carbachol (10(-5) M) reached a maximum 15 min. after addition and then remained almost constant. Cocaine (3 x 10(-5) M) did not alter the effect of acetylcholine. Desipramine (10(-6) M) and corticosterone (4 x 10(-5) M) attenuated the inhibition seen with low concentrations (10(-8)-10(-7) M) of acetylcholine. The acetylcholine-induced inhibition was antagonized by desipramine. Cocaine plus corticosterone attenuated the inhibition seen with high concentrations (10(-6)-3 x 10(-6) M) of acetylcholine. Rauwolscine (10(-6) M) enhanced the maximal inhibitory effect of acetylcholine. We conclude that the inhibitory effect of acetylcholine on 3H-overflow from rabbit aorta preloaded with 3H-noradrenaline is (1) inversely related to stimulation frequency; (2) independent of endothelium; (3) unaffected by neuronal and extraneuronal transmitter uptake; (4) that cocaine is not a prejunctional muscarinic antagonist; (5) that cocaine, but not desipramine, is suited as a neuronal uptake inhibitor in studies of prejunctional muscarinic receptor subtypes; and (6) and that there is an inverse interaction between prejunctional alpha2-adrenoceptors and muscarinic receptors.

Acetylcholine↗
PubMed1986

Characterization of xylamine binding to proteins of PC12 pheochromocytoma cells.

PC12 pheochromocytoma cells take up 3,4-dihydroxyphenylethylamine (dopamine) and norepinephrine by a Na+-dependent, cocaine-sensitive system. The kinetics suggest that the same transporter functions for both substrates. Xylamine, a nitrogen mustard that blocks catecholamine uptake into neurons, irreversibly inhibited norepinephrine uptake into PC12 (IC50 = 15 microM). Pretreatment with 10 microM xylamine did not inhibit norepinephrine transport if 10 microM cocaine or 100 microM norepinephrine was also present during the pretreatment period or if Na+ was absent. These results indicate that xylamine must interact with the norepinephrine transporter to inhibit norepinephrine uptake. PC12 accumulated [3H]xylamine; this uptake had Na+-dependent and Na+-independent components. The Na+-dependent uptake was saturable (Km = 13 microM), and it was inhibited by cocaine (IC50 = 0.6 microM), desipramine (IC50 less than 1 nM), and norepinephrine (IC50 = 1 microM). Several proteins became prominently labeled when intact PC12 cells were incubated with [3H]xylamine; these proteins were enriched in a plasma membrane fraction and have molecular weights of 17,000, 24,000, 31,000, 33,000, 41,000, 42,000, 52,000, and 80,000. Other proteins were labeled less prominently. The labeling of all proteins was markedly decreased when the incubation with [3H]xylamine occurred in the presence of cocaine, desipramine, gramicidin D, or in a Na+-free buffer. These results indicate that xylamine must be transported into the cells for covalent binding to proteins to occur. [3H]Xylamine labeled essentially the same proteins when incubated with cell homogenates, but competition experiments with bretylium, desipramine, and cocaine failed to reveal which of the [3H]xylamine-labeled proteins is associated with the norepinephrine transporter.

Adrenal Gland Neoplasms↗
PubMed1990

Reduction in beta-adrenoceptor density in cultured rat glioma C6 cells after incubation with antidepressants is dependent upon the culturing conditions used.

The hydrophilic beta-adrenoceptor ligand (-)-[3H]CGP-12177 binds to intact C6 cells with a high affinity (KD approximately 0.1 nM) and with a high degree of specificity. The binding was inhibited by DL-propranolol (Ki approximately 1 nM). Treatment of cells cultured in Dulbecco's modified Eagle medium (DMEM) without fetal calf serum for 4 days with desipramine reduced the (-)-[3H]CGP-12177 specific binding in a concentration-dependent manner, a reduction from 127 to 102 fmol/mg of protein being found at a ligand concentration of 1 nM after treatment with 10 microM desipramine. Lesser effects were seen after treatment for 1 day. A similar result was found with maprotiline, and reductions in specific binding were seen after 4 days of treatment with amitriptyline, iprindole, and citalopram. The reduction in binding-site density (measured per milligram of protein to compensate for variability in cell density per well), however, was paralleled in all cases by a reduction in the rate of cell proliferation. When C6 glioma cells were cultured in Ham's medium without fetal calf serum during the antidepressant treatment period, a higher specific binding was observed than for the DMEM-cultured cells, and 10 microM desipramine was without effect on either the (-)-[3H]CGP-12177 specific binding or cell proliferation. It is concluded that the effects of the antidepressants tested upon the density of (-)-[3H]CGP-12177 specific binding sites in intact C6 cells may be secondary to the toxicity of the compounds under the conditions used.

Adrenergic beta-Antagonists↗
PubMed1991

A microdialysis study of the regulation of endogenous noradrenaline release in the rat hippocampus.

In vivo microdialysis was used to investigate the regulation of noradrenaline release in rat hippocampus. Idazoxan, an alpha 2-adrenoreceptor antagonist (1-10 mg/kg), increased noradrenaline release in a dose-dependent manner. Inhibition of noradrenaline uptake by desipramine (0.05-20 microM; via the probe) also increased the extracellular content of the transmitter. In the presence of this increased noradrenaline content (desipramine via the probe), the effect of a low dose of idazoxan (1 mg/kg) was potentiated. Local perfusion of idazoxan (1-500 microM) in the hippocampus also increased noradrenaline release but not to the same extent as following systemic administration. In the presence of desipramine, unlike the systemic injection of idazoxan, local perfusion did not potentiate noradrenaline release. The data are consistent with the regulation of extracellular noradrenaline content in the hippocampus by neuronal uptake and to a lesser extent by presynaptic autoreceptors.

Adrenergic alpha-Antagonists↗
PubMed1969

Effects of phenoxybenzamine on the uptake and metabolism of noradrenaline in the rat heart and vas deferens.

1. In the isolated rat heart perfused with various concentrations of (+/-)-(3)H-noradrenaline ((3)H-NA) the addition of phenoxybenzamine, cocaine or desipramine to the perfusion medium resulted in an inhibition of (3)H-NA uptake which appeared on kinetic analysis to be of a competitive nature.2. Phenoxybenzamine also blocked the formation of labelled metabolites of (3)H-NA in the heart at all perfusion concentrations of (3)H-NA; this effect appeared to be unrelated to the inhibition of the neuronal uptake of NA produced by phenoxybenzamine, since no blockade of (3)H-NA metabolism was produced by cocaine in similar experiments.3. In slices of rat vas deferens incubated with various concentrations of (3)H-NA, cocaine and desipramine and phenoxybenzamine were also shown to act as competitive inhibitors of NA uptake. Cocaine and phenoxybenzamine were less potent inhibitors of uptake in the vas deferens than they were in the heart; desipramine was equally potent in both tissues.4. When vas deferens slices were incubated in a medium containing phenoxybenzamine for 30 min before the addition of (3)H-NA, the resulting inhibition of (3)H-NA uptake was increased and changed to a non-competitive type of interaction.5. In hearts or vasa deferentia taken from animals pretreated in vivo with phenoxybenzamine (20 mg/kg), a significant inhibition of (3)H-NA uptake was found when the tissues were exposed to low concentrations of (3)H-NA but not when higher concentrations of (3)H-NA were used.

Animals↗
PubMed1977

The sympathomimetic activity of fenfluramine hydrochloride on rat vas deferens.

1. The peripheral, pharmacological effects of the anorexigenic agent, fenfluramine hydrochloride, have been investigated on rat isolated vas deferens. 2. Characteristic spiked contractions were observed within 2 to 3 min after exposure to fenfluramine; these contractions reached a rate of around 13 per min and were of variable height. 3. Pre-treatment of vasa with the indirectly acting sympathomimetic amine, tyramine, greatly reduced both the height and rate of contraction induced by fenfluramine. 4. The uptake inhibitor, desipramine, required a concentration in excess of 10 micronM to affect fenfluramine-induced contractions. Effects of desipramine on fenfluramine contractions were of equal magnitude whether desipramine was administered before fenfluramine or at the height of the fenfluramine-induced contractions. 5. Pre-treatment with debrisoquine (0.5 mM), reduced the contractions in response to fenfluramine over a period of time. 6. Fenfluramine, added to vasa from rats which had been injected intraperitoneally with 5 mg/kg reserpine 24 h and 48 h previously, failed to induce its characteristic contractions. 7. It is concluded that fenfluramine can be classed as an indirectly acting sympathomimetic amine on peripheral adrenergic nerve terminals.

Animals↗
PubMed1985

Frequency-dependent block of field potentials in the rat hippocampal slice caused by tricyclic antidepressants.

The effect of the tricyclic antidepressants imipramine and desipramine were studied on field potentials in the rat hippocampal slice. The electrically evoked stratum radiatum nerve volley, excitatory postsynaptic potential (e.p.s.p.) and pyramidal cell layer population spike (PS) were recorded in the CA1 region. At concentrations of 10(-6)M to 10(-5)M, impramine did not affect the amplitude of the nerve volley, e.p.s.p. or PS at low frequencies of stimulation (0.01 Hz). At higher frequencies of stimulation (1-100 Hz), imipramine caused a frequency-dependent block of the nerve volley, e.p.s.p. and PS. The time course of onset of the frequency-dependent block in the presence of imipramine was very slow. Maximum inhibition was reached after 3-4 h treatment with imipramine. Desipramine (10(-6)-10(-5)M) also caused a frequency-dependent block of the hippocampal field potentials. Only slight frequency-dependent block was observed in slices from rats injected in vivo with desipramine (10 mg kg-1) for 14 days.

Action Potentials↗
PubMed1987

Independent regulation of beta 1- and beta 2-adrenoceptors.

1 The down-regulation of beta-adrenoceptors has been postulated as a biochemical marker of antidepressant efficacy. Here we demonstrate that chronic treatment with desipramine down-regulates beta 1-adrenoceptors in rat cerebral cortex and that beta-adrenoceptor subtypes can be independently regulated by treatment with different beta-adrenoceptor agonists. 2 Desipramine, (+/-)-clenbuterol, prenalterol, corwin (20 mg kg-1 daily) and corwin (10 mg kg-1 daily) were administered to male, Sprague-Dawley rats, over eight days, by means of osmotic Alzet pumps placed subcutaneously and removed 24 h before analysis. Control rats received vehicle only. The beta 1- and beta 2-adrenoceptor populations were measured in cerebral cortex by a modified (-)-[125I]-pindolol receptor binding assay. 3 The conventional antidepressant, desipramine, preferentially down-regulated beta 1-adrenoceptors whereas the non-selective beta-adrenoceptor agonist (+/-)-clenbuterol preferentially down-regulated beta 2-adrenoceptors. The beta 1-selective partial agonist, prenalterol, up-regulated beta 1-adrenoceptors perhaps acting more as an antagonist than as an agonist. Finally, neither dose of corwin had any significant effect on beta-adrenoceptor number.

Adrenergic beta-Agonists↗
PubMed1988

4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH): a new potentiator of sympathomimetic amines on the rat anococcygeus muscle.

1. The potentiating effects of racemic 4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH), cocaine, desipramine and nomifensine on the concentration-response curves of the rat anococcygeus muscle to noradrenaline (NA) and field stimulation were examined. 2. PI-OH and cocaine concentration-dependently potentiated the responses of anococcygeus muscle to NA and field stimulation, but the activity of PI-OH was stronger than that of cocaine on both responses. 3. At high concentrations the potentiating activities of desipramine and nomifensine were less, a fact that was explained by their postsynaptic inhibitory properties; the actions of nomifensine and desipramine as antagonists against NA were competitive and non-competitive, respectively. 4. It is concluded that PI-OH may be an ideal potentiator of the response to NA in adrenergically-innervated tissues because it has no side effects such as postsynaptic inhibition.

Animals↗
PubMed1981

Specific norepinephrine and serotonin uptake inhibitors in man: a crossover study with pharmacokinetic, biochemical, neuroendocrine and behavioral parameters.

Eight depressed patients with major affective illness were treated with both zimelidine, a selective serotonin-uptake inhibitor, and with desipramine, a selective norepinephrine uptake inhibitor, following a double-blind crossover design. At steady-state the active metabolite of zimelidine, norzimelidine, predominated in the CSF by a factor of 7 to 1 over parent drug. As predicted, even high concentrations of norzimelidine were not associated with decreased 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the CSF. In the same individuals, desipramine concentrations were highly correlated with decreases of MHPG in the CSF. Despite specific effects on monoamine neurotransmitter systems which have been implicated in the control of neuroendocrine secretion, neither drug had consistent effects on plasma cortisol, luteinizing hormone, growth hormone or prolactin. Both drugs had a marked and unexpected common effect on the 24-hour rest-activity cycle. The excess activity during the normal rest period (0--700 hr.) which has been noted in severely depressed individuals was significantly reduced by both the serotonergic zimelidine and the noradrenergic desipramine. These findings suggest that effects on the rest-activity pattern may be a common pathway for antidepressant effect.

Adolescent↗
PubMed1975

Tricyclic antidepressant agents. II. Effect of oral administration on the uptake of 3-H-noradrenaline and 14-C-5-hydroxytryptamine in slices of the midbrain-hypothalamus region of the rat.

The inhibition of the simultaneous uptake of 3-H-l-noradrenaline (NA) and 14-C-5-hydroxytryptamine (5-HT) in slices of the midbrain-hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5-HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5-HT uptake (ED50 = 35 mg/kg orally) as on the NA uptake (ED50 = 20mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED50 greater than 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED50 = 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED50 values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5-HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED50 = 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre-treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of 14-C-imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the5-HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED50 = 11 mg/kg intraperitoneally).

Administration, Oral↗
PubMed1987

Acute effects of nomifensine on in vivo uptake and metabolism of dopamine, noradrenaline and serotonin in the rat brain.

Nomifensine, in contrast to all other antidepressants, inhibits the neuronal uptake of dopamine. The effect of this drug (10 mg/kg intraperitoneally) on the metabolism of dopamine, serotonin and noradrenaline was studied in the rat brain. After 1.5 hours, nomifensine increased the concentrations of homovanillic acid (HVA) in corpus striatum and total (free and conjugated) 3-methoxy, 4-hydroxyphenylglycol (MOPEG) in mesencephalon, but had no effect on the 5-hydroxyindoleacetic acid (5-HIAA) in pons/medulla oblongata and mesencephalon. The effect was identical with that of desipramine (25 mg/kg) on MOPEG and of imipramine (25 mg/kg) on 5-HIAA. Two methods ordinarily used for estimating turnover rates of monoamines were compared: accumulation of acid metabolites after probenecid (measuring efflux of metabolites from the brain) and accumulation of monoamine precursors after decarboxylase inhibition (measuring amine synthesis). The efflux was reduced for 5-HIAA and MOPEG but increased for HVA after nomifensine. Imipramine had the same effect on 5-HIAA and desipramine on MOPEG. Desipramine decreased the efflux of HVA from corpus striatum. In contrast, nomifensine did not change the synthesis of noradrenaline and serotonin significantly. Imipramine reduced the synthesis of serotonin in pons/medulla oblongata. In corpus striatum nomifensine, unlike imipramine, increased the concentration of 5-HIAA and synthesis of serotonin in spite of a decrease in efflux, probably because of a secondary effect from the dopaminergic action. The conclusion was made that there were more than one compartment of monoamine metabolites. The antidepressants could to some extent lead to a shift in the metabolism to sites more distant to the transport mechanism.

Animals↗
PubMed1988

Neonatal treatment with monoamine uptake inhibitors alters later response in behavioural 'despair' test to beta and GABA-B receptor agonists.

The administration of monoamine uptake-inhibiting antidepressant drugs to rats during the early postnatal period was previously shown to lengthen the duration of subsequent immobility in Porsolt's swim test, hence suggesting increased behavioural 'despair' in these animals. Because the mechanism of the antidepressant action may be related to changes in the cerebral monoamine or gamma-aminobutyric acid (GABA) function, the present study was carried out to examine the response in the swim test to a beta-receptor agonist salbutamol, or to the GABA-B receptor agonists progabide and baclofen in rats treated with antidepressant drugs during the second and third postnatal week: either desipramine 5 mg/kg, nomifensine 10 mg/kg or zimeldine 25 mg/kg. When tested a month later i.e. at the age of two months these rats were immobile in water for a longer period than the controls. Salbutamol 10 mg/kg and progabide 100 mg/kg increased the immobility time in the control rats but neither drug affected the rats treated with desipramine, nomifensine or zimeldine. When the animals were 5 months of age, salbutamol 10 mg/kg and baclofen 10 mg/kg shortened the immobility time in the desipramine-treated rats. The control rats and those treated with zimeldine were not affected by the drugs. The results indicate that in the rats which were neonatally treated with antidepressants, the immobility time in water is lengthened in adulthood. Moreover, the response to beta-receptor and GABA-B receptor agonists is increased from the response observed in the control rats.

Albuterol↗
PubMed1979

Release of 3H-noradrenaline from the rat vas deferens under various in vitro conditions.

The release of 3H-(-)-noradrenaline (NA) from rat vas deferens in vitro was examined under various experimental conditions. It was found that in normal and reserpinized vas deferens the release of NA evoked by (+)-amphetamine (5 X 10(-6) M) or low external Na+ (26 mM) was antagonized by imipramine methiodide and desipramine, inhibitors of the NA uptake, but was not dependent on the presence of Ca2+ in the medium and was not antagonized by the potent local anaesthetic agent bethoxycaine. The release evoked by veratridine in reserpinized tissue was antagonized by the uptake inhibitors but was in normal tissue only partially inhibited in presence of Ca2+ but almost completely in absence of Ca2+. The release by high K+ (117 mM)+low Na+ (26 mM) in normal tissue was dependent on the presence of Ca2+ and was antagonized by the muscarinic agonists carbacholine and metacholine and by high concentrations of desipramine. In the reserpinized vasa the corresponding release was not dependent on Ca2+ and was not antagonized by the muscarinic agents but was inhibited by high concentrations of desipramine.

Aminobenzoates↗
PubMed1985

Effect of phenobarbitone on the distribution and elimination of imipramine in rats.

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg-1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot,b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t1/2) and Vdss significantly decreased to approximately 23-40% while CLtot,b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were less than 1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.

Animals↗