Ibopamine kinetics after a single oral dose in patients with congestive heart failure.

The kinetics of ibopamine, the 3,4-diisobutyryl ester of N-methyldopamine (epinine), was assessed in 27 patients with congestive heart failure (CHF) and 8 healthy normal subjects (NS). Nine patients were in functional class IV according to the NYHA definition, 9 in class III and 9 in class II. Ibopamine was administered at a single oral dose of 100 mg. Epinine, both free and total (mainly conjugated), plasma concentrations and urinary recoveries of total epinine, HVA and DOPAC were studied. The results showed that ibopamine kinetics is not substantially different in CHF patients and in NS. In both groups the absorption of the drug was equally prompt and elevated. Mean Cmax, tmax and AUC infinity values of total epinine in CHF patients did not differ significantly from those in NS. In CHF patients t 1/2 of total epinine was significantly higher than in NS (4.1 +/- 0.2 h vs 3.1 +/- 0.2 h, mean +/- SE). Mean Cmax, tmax, AUCt and MRT values of free epinine in CHF patients were not significantly different from those in NS. The urinary recovery of the 3 metabolites considered together was comparable in CHF patients and in NS. The mean +/- SE total urinary recoveries in the 24 h after dosing, expressed as percentages of the administered dose, were 60 +/- 3 in CHF patients and 69 +/- 4 in NS. Conjugated epinine in urine was found to be constituted by 3-O-sulfate (84%) and 4-O-sulfate (16%).

Pharmacokinetics of ibopamine in patients with renal impairment.

The pharmacokinetics of a single oral dose of ibopamine 100 mg were studied in 15 patients with various degrees of chronic renal impairment (CRI) and in 8 subjects with normal renal function and of comparable age, taken as a control group. Plasma total (mainly conjugated) and free epinine and urinary metabolites (total epinine, HVA and DOPAC) were measured. Both total and free epinine were detectable at the earliest sampling time (15 min) in CRI patients and in normal subjects, thus confirming the promptness of ibopamine absorption. Free epinine pharmacokinetic parameters did not show any appreciable differences among the groups with different degrees of renal impairment, and no statistically significant differences were observed between normal subjects and CRI patients. Progressive renal impairment was associated with higher Cmax, longer t1/2 and larger AUC infinity of total epinine, and with reduced urinary elimination of total epinine and metabolites. Statistically significant differences (p less than 0.01) in Cmax/70 kg, t1/2, and AUC infinity/70 kg of total epinine were found between normal subjects and patients with mild renal impairment. No statistically significant differences were observed in 24-h urinary recoveries of both total epinine and metabolites between normal subjects and patients with mild renal impairment. No adverse effects were experienced during the course of the study. As the kinetics of ibopamine's active moiety, free epinine, were not apparently altered by chronic renal failure, adjustment of its dosage should not be necessary in renal diseases.

Ibopamine, an orally active dopamine-like drug: metabolism and pharmacokinetics in rats.

Ibopamine (SB-7505), the 3,4-diisobutyrylester of N-methyldopamine (epinine), was rapidly hydrolyzed to epinine by plasma esterases of rat as well as of other animal species and man. Ibopamine was rapidly and extensively metabolized after oral administration to rat. Plasma levels of free epinine peaked at 30-60 min from the administration; conjugated epinine was present in larger amount, with a maximum at 3 h. Both free and conjugated epinine were still detectable at 6 h, but not at 24 h. Epinine 4-O-glucuronide, 4-hydroxy-3-methoxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid appeared as main urinary metabolites; epinine 3-O-sulphate, epinine 3-O-methylether and its glucuronide, and trace amounts of epinine 4-O-sulphate were also detected.

Ibopamine, an orally active dopamine-like drug: metabolism and pharmacokinetics in dogs.

Ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine (epinine), exerts, on oral administration, cardiovascular effects similar to those of intravenously infused dopamine. Plasma levels and urinary excretion of metabolites were investigated in dogs after oral administration of 4 mg/kg of ibopamine hydrochloride. Epinine, which was readily formed from ibopamine by esterases hydrolysis, was present in plasma in free and sulphate-conjugated form. The urinary metabolites after 6 h from the administration amounted to 62% of the dose, as a sum of 37% of epinine 3-O-sulphate, and 15 and 10% of 4-hydroxy-3-methoxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid, respectively, both in free and conjugated form. When the main metabolite, epinine 3-O-sulphate, was administered intravenously it appeared to be excreted in urine without being deconjugated to any detectable extent, while it appeared to be partially deconjugated on oral administration.

Ibopamine kinetics after a single oral dose in healthy volunteers.

In order to describe kinetics after single administration and to test dose independence in the therapeutic dose range, ibopamine (SB-7505), the 3,4-diisobutyrylester of N-methyldopamine (epinine), was given orally to six healthy volunteers at multiple dose levels in a cross-over fashion. Doses employed were 50, 100 and 200 mg with a wash-out period of at least three days between doses. Plasma levels were studied after the 100 mg dose, and urinary recoveries of the major metabolites were measured after each dose. After oral intake of ibopamine, both conjugated and free epinine were detectable in plasma at the earliest sampling times (i.e. 5-10 min), with a hybrid absorption half-life of 0.25 h. Peak plasma concentration mean values of total and free epinine were 33 mumol/l and 35 nmol/l, respectively, and mean time to plasma peak concentration was 1.5 and 0.71 h, respectively. 24-h urinary recovery of conjugated epinine, homovanillic acid and dihydroxyphenylacetic acid accounted for about two thirds of the dose, without dose-dependent mechanisms affecting total elimination. Presystemic sulfate conjugation as a potentially saturable metabolic step at higher dose levels is discussed, although evidence was not found of its saturation in the studied dose range.

Evaluation of acute hemodynamic effects and pharmacokinetic behaviour of ibopamine in patients with severe heart failure.

The aim of the present investigation was to evaluate the acute hemodynamic effects of a single oral dose of 200 mg ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine (epinine) in 11 patients with congestive heart failure (CHF) and to compare the influence of dopamine infusion and oral ibopamine on left ventricular function. Free and conjugated epinine plasma levels were also investigated in these patients and in a group of healthy volunteers to evaluate the correlation between epinine plasma levels and hemodynamic effects. The oral administration of 200 mg ibopamine to patients with CHF, increased cardiac index (+35%) and reduced peripheral and pulmonary vascular resistance (-29% and -26%) without modifying heart rate and systemic or pulmonary arterial pressure. The hemodynamic effect reached its maximum at about 90 min and was still present at 240 min. Ibopamine at a dose of 200 mg elicited similar effects to those observed with dopamine, 2-4 micrograms/kg/min. The pharmacokinetic behaviour of ibopamine in these patients was similar to that observed in a group of healthy volunteers. Free epinine plasma levels peaked at 30-60 min and decreased rapidly, thus showing a shorter time course than the hemodynamic effects.

Effects of m-chlorophenylpiperazine on receptor binding and brain metabolism of monoamines in rats.

m-Chlorophenylpiperazine (mCPP) was studied for its ability to displace the binding of (3)H-ligands for monoamines to brain membranes and its effect on monoamine metabolism in various brain areas of the rat. mCPP displaced (3)H-serotonin binding to cortex membranes (Ki = 10(-7) M) but had virtually no effect on (3)H-spiroperidol binding to striatal membranes used as ligand for dopamine receptors (Ki > 10(-5) M). mCPP showed Ki values very similar to those of noradrenaline in displacing the binding of (3)H-WB 4101 (2-2,6-dimethoxy-phenoxy-ethylaminomethylbenzodioxan) and (3)H-DHA ((3)H-dihydroalprenolol), used as ligands for alpha(1) and beta adrenergic receptors respectively. At 0.3 and 1 mg/kg, mCPP preferentially reduced serotonin metabolism (decrease of 5-hydroxy-indoleacetic acid level) in various brain areas but at 3 and 10 mg/kg it raised homovanillic levels in the striatum and nucleus accumbens and 3-methoxy-4-hydroxyphenylethylene glycol sulphate levels in the brain as well. The data are compatible with the hypothesis that at lower doses mCPP preferentially acts by mimicking the action of serotonin on postsynaptic receptors. It is suggested that the effects on dopamine metabolism observed with higher doses might be mediated by the action of mCPP on brain serotonin, whereas direct action on central noradrenaline-containing neurons could contribute to the increase of noradrenaline metabolism.

Further studies on the mechanism of serotonin-dependent anorexia in rats.

4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.

Effects of narcotic analgesics on the uptake and release of 5-hydroxytryptamine in rat synaptosomal preparations.

1 The effects of various narcotic analgesics on the uptake and release of labelled 5-hydroxytryptamine (5-HT) in brain and spinal cord synaptosomes were investigated.2 Methadone was most active in inhibiting 5-HT uptake (IC(50) 2.5 x 10(-7) M). Levorphanol also inhibited 5-HT uptake to a large extent (IC(50) 8.8 x 10(-7) M) while dextrophan, pethidine and pentazocine showed much less activity. Etorphine and morphine had virtually no such activity, with IC(50)S higher than 10(-4) and 10(-3) M respectively.3 The same order of potency as ;5-HT releasers' was found when radioactivity was measured in [(3)H]-5-HT preloaded synaptosomal pellets incubated for 20 min with the various narcotics. Methadone, like chlorimipramine, showed a significant effect at a concentration of 10(-7) M while morphine, at a concentration of 10(-4) M, had no effect.4 When 5-HT release was studied by a perfusion technique, which largely prevents reuptake of the released amine, only fenfluramine, an anorectic agent proposed as a 5-HT releaser, significantly increased spontaneous 5-HT release. These data suggest that the apparent 5-HT release induced by various narcotics in traditional incubation techniques may largely depend on their ability to interfere with neurotransmitter reuptake mechanisms.5 The effects of the various narcotics on 5-HT uptake have no relationship to their relative potency as analgesics in the rat. In the light of their poor effectiveness as 5-HT releasers, it can be concluded that mechanisms other than 5-HT uptake inhibition and release are probably involved in the analgesic effects of these compounds in intact animals.