Plasma Concentrations Of Dopamine Research Articles

Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs

Pharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N-(N-acetyl-L-methionyl)0,0-bis-eth-oxycarbonyl) dopamine(1). Plasma concentrations of DA, DA-SO4, and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first-pass metabolism for the formation of DA-SO4 and DOPAC. Though plasma concentration of DA was quite different from that of DA-SO4 or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA-SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N-(N-acetyl-L-methionyl)dopamine(2), DA-SO4, and DOPAC after oral administration of 1 were simultaneously analysed using the compartment model including the first-pass metabolism and two-fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of 2(K4) is larger than that of DA-SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially played an important role to the reduction of first-pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of reduction of first-pass metabolism of DA.

Interactions of Nimodipine and Cocaine on Endogenous Catecholamines in the Squirrel Monkey

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.

Tissue and plasma levels of a teratogenic dose of dopamine in the chick embryo following pretreatment with metoprolol or phosphate buffered saline

Metoprolol pretreatment has been shown to reduce the cardiovascular malformation rate produced by topical doses of dopamine in the stage 24 chick embryo. We report on the tissue and plasma levels and teratogenic effect of dopamine hydrochloride following topical application of a teratogenic dose in stage 24 chick embryos pretreated with either metoprolol tartrate or phosphate buffered saline (PBS). Pretreatment with either metoprolol or PBS resulted in similar patterns of dopamine distribution in the head, body, and heart, with peak levels occurring at 12 hours after dopamine treatment. Plasma concentrations of dopamine were similar for both PBS and metoprolol pretreated embryos, with plasma levels exceeding tissue concentrations, but also peaking at 12 hours after dopamine treatment. Pretreatment with PBS followed by a teratogenic dose of dopamine resulted in a decrease in the teratogenic effect of dopamine similar to that found in previous work in our lab with pretreatment with metoprolol. The developing chick cardiovascular system experiences peak susceptibility to the teratogenic effects of dopamine at stage 24 during development, which represents a time frame of about 12 hours. A delay in the peak levels of dopamine to 12 hours after dopamine treatment as compared to previous work in our lab reporting peak levels of dopamine at 1 hour, suggests that the previously reported antiteratogenic effects of metoprolol may be due, at least in part, to a delayed absorption of dopamine past the time of peak susceptibility of the embryo to the teratogen.

Plasma noradrenaline and dopamine in renin‐mediated hypertension

Noradrenaline (NA) and dopamine (DA) have opposite effects on the kidney; NA causes vasoconstriction and increased sodium reabsorption while DA promotes vasodilation and natriuresis. In 15 patients investigated for renin-mediated hypertension measurements of plasma renin activity (PRA), NA and DA concentrations were made in arterial and renal venous blood from both kidneys before and after acute stimulation of renin release by i.v. dihydralazine. Nine patients had unilateral renin secretion and were classified as renin-positive, while the remaining six patients were renin-negative. Renin-positive patients had higher arterial and renal venous PRA, NA and DA levels than the negative ones. In the renin-positive group V-A differences for NA and DA were present on both sides despite unilateral secretion of renin. NA but not DA levels were higher in the renin-secreting kidney, which can partly be explained by the reduced plasma flow to the involved kidney. After dihydralazine the arterial NA and DA rose similarly in renin-positive and renin-negative patients, while PRA rose only in the renin-positive cases. In the renin-positive patients where stimulation of renin secretion caused a marked increase of the PRA gradient on the affected side only, renal gradients for NA and DA increased bilaterally. The increase in DA was more pronounced than that of NA yielding a rise in DA/NA ratio on the affected side. Arterial PRA was positively correlated to the plasma concentrations of NA and DA. V-A differences for PRA and NA or DA were positively correlated on the involved renin-secreting side. In summary, patients with renin-dependent hypertension have elevated plasma NA and DA concentrations. Stimulation of renin release by dihydralazine increases the DA/NA ratio in arterial and renal venous blood indicating release of 'precursor dopamine' from noradrenergic fibres and/or activation of dopaminergic nerves. There seems to be a relationship between renal nerve activity and renin release in renin-dependent hypertension.

Direct pituitary inhibition of prolactin secretion by dopamine and noradrenaline in sheep

The effects of dopamine, noradrenaline and 3,4-dihydroxyphenylacetic acid (DOPAC) on the release of prolactin were examined in ovariectomized ewes. Infusion of dopamine (0.5 or 1 microgram/kg per min for 2 h i.v.) reduced plasma prolactin concentrations in a dose-dependent manner, whereas DOPAC (5 or 10 micrograms/kg per min for 2 h i.v.) had no effect. In a further series of experiments, ovariectomized hypothalamopituitary disconnected ewes were given dopamine or noradrenaline (each at 0.5 or 1 microgram/kg per min for 2 h i.v.), and both amines reduced mean plasma concentrations of prolactin with similar potency in a dose-dependent manner. These effects were blocked by treatment with pimozide and prazosin respectively. During the infusion of dopamine, the peripheral plasma concentrations of DOPAC and 3,4-dihydroxyphenylethyleneglycol (DHPG) were increased (DOPAC, 22 +/- 7 (S.E.M.) to 131 +/- 11 nmol/l; DHPG, 2.9 +/- 0.3 to 6.4 +/- 0.2 nmol/l), but plasma concentrations of dopamine and noradrenaline did not change. Finally, administration of domperidone, a specific dopamine receptor antagonist that does not cross the blood-brain barrier, resulted in a sustained increase in plasma prolactin concentrations in ovariectomized ewes. We conclude that the secretion of prolactin from the pituitary gland is under dual inhibitory regulation by both dopamine and noradrenaline in the sheep.

Bioavailability and Pharmacokinetics of an Oral Dopamine Prodrug in Dogs

The bioavailability and pharmacokinetics of an oral dopamine prodrug, N-(N-acetyl-L-methionyl)O,O-bis(ethoxycarbonyl)dopamine (1), were examined in dogs, and the mechanism of its absorption and bioactivation was discussed. Compound 1 showed a plasma dopamine concentration that was several times higher than that of dopamine (DA) following oral administration to dogs, while the plasma concentrations of dopamine-30-sulfate (DA-SO4) and 3,4-dihydroxyphenylacetic acid (DOPAC) are lower in comparison with that of DA. The conversion of 1 to DA occurred in proportion to the dose administered. Compound 1 also showed a plasma DA concentration that was several times higher than that of other DA prodrugs reported hitherto. In dog plasma, in vitro, 1 was converted to its deethoxycarbonylated form, N-(N-acetyl-L-methionyl)dopamine (2), while other related compounds, N-(L-methionyl)dopamine (3), N-(L-methionyl)O,O-bis(ethoxycarbonyl)-dopamine (4), and O,O-bis(ethoxycarbonyl)dopamine (5), were rapidly converted to DA (however, 2 was stable in plasma). Bioavailability, based on the AUC of DA, 1, 2, and 5 following oral administration to dogs, increased in the following order: 1, 2, 5, and DA. Thus, it was shown that the two protective groups introduced in 1 served to reduce the first-pass metabolism of the DA moiety in the absorption process. It was also confirmed that 1 is converted to 2 or DA in blood, liver, and intestine.

Effects of glucocorticoids on plasma catecholamines in depression

To explore corticosteroid-catecholamine interactions in depression, plasma dopamine, norepinephrine, and epinephrine concentrations were studied both before and after dexamethasone in 16 patients during depression and after recovery, and in 28 healthy controls. Dexamethasone had a significant suppressive effect on plasma epinephrine levels in depressed patients and controls, while dopamine and norepinephrine levels were not significantly affected following dexamethasone administration. Levels of norepinephrine, epinephrine, and cortisol were positively correlated, while dopamine showed no correlation with cortisol values. These findings point to differentiated interrealations between certain catecholamines and glucocorticoids which possibly are affected during depressive illness.

The role of dopamine in nonmodulating hypertension.

Dopamine may exert a tonic inhibitory effect on aldosterone secretion and enhance renal sodium excretion. Nonmodulating hypertension in part is characterized by decreased aldosterone secretion in response to angiotensin II (AII) as well as a decreased natriuretic response to a saline load. This study assesses whether an abnormally increased dopaminergic inhibition of aldosterone secretion underlies the adrenal defect in nonmodulating hypertension and whether abnormalities of renal dopamine formation contribute to sodium retention. We measured the plasma dopamine concentration in 39 patients with nonmodulating hypertension and in 32 patients with normal modulation on a 10-meq sodium intake. Dopamine levels were significantly higher (P less than 0.05) in nonmodulators. The aldosterone response to AII (3 ng/kg.min) was assessed before and during administration of the dopamine antagonist metoclopramide in 13 patients. Metoclopramide did not change the adrenal response to AII in either hypertensive subgroup. In 12 normal subjects mean urinary dopamine levels were higher in a sodium-replete state (200-mmol intake) than in a low sodium state (10-mmol intake; 1.68 +/- 0.28 vs. 0.92 +/- 0.22 mumol/day; P less than 0.01) as expected. Modulators demonstrated this same effect, while nonmodulators did not [modulators, 3.66 +/- 0.82 and 1.37 +/- 0.14 mumol/day; nonmodulators, 1.33 +/- 0.28 and 1.68 +/- 0.90 mumol/day; P less than 0.02]. The sodium-retaining tendency of nonmodulators may reflect, at least in part, reduced intrarenal dopamine production in the sodium-replete state, but the adrenal defect in aldosterone release in nonmodulators is not mediated by excess dopaminergic inhibition of aldosterone secretion.

A Novel Orally Active Dopamine Prodrug TA-870. I. Renal and Cardiovascular Effects and Plasma Levels of Free Dopamine in Dogs and Rats

Intraduodenal administration of N-(N-acetyl-L-methionyl)-O, O-bis(ethoxycarbonyl)dopamine (TA-870), a newly synthesized dopamine derivative, increased the renal blood flow (RBF) and mesenteric blood flow in anesthetized dogs, while blood pressure and heart rate were less affected. It also increased the glomerular filtration rate, urine volume, and urinary sodium excretion in saline-loaded anesthetized dogs. In conscious dogs, TA-870 and dopamine hydrochloride (DA-HCl) increased RBF in parallel with increases in plasma free dopamine (free-DA) concentration. At an equimolar dose of 71 mumols/kg, p.o., the effect of TA-870 continued for greater than 4 h, while that of DA-HCl lasted for only 2 h: the peak free-DA concentration and maximum increase in RBF were 155 +/- 57 ng/ml and 56 +/- 15%, respectively, for TA-870, and those for DA-HCl were 32 +/- 13 ng/ml and 36 +/- 10%. Similarly, TA-870 showed greater increases in both RBF and plasma free-DA concentration than DA-HCl in anesthetized rats. In contrast to enteral administration, intravenously administered TA-870 exhibited weaker effects than intravenous DA-HCl in anesthetized dogs. In conclusion, TA-870 is an orally effective dopamine prodrug capable of producing higher and more sustained plasma concentrations of dopamine than DA-HCl when administered by the enteral route.

Determination of Exogenously Administered Dopamine in Infant Plasma Using Liquid Chromatography with Electrochemical Detection

Abstract A simple, rapid liquid chromatography method is described for the measurement of exogenously administered dopamine in infant plasma, using electrochemical detection and 3,4 dihydroxybenzylamine hydrobromide as the internal standard (IS). The mobile phase consisted of a monochloroacetate buffer (pH=3.0) with sodium octyl sulfate as the ion-pairing agent, and 2.5% acetonitrile. A biophase IIR reverse phase column was used, and the electrochemical detector was set at +650 mV versus Ag/AgCl. The retention times of IS and dopamine were 3.3 and 6.5 minutes, respectively. The recovery of dopamine following an alumina extraction procedure ranged from 75 to 80%. The inter- and intra-day coefficients of variation using this method were less than 10% and less than 5%, respectively. The major advantages of this method include use of a very small volume of plasma sample (20 μl) and ability to determine very wide ranges of plasma concentrations of dopamine following its administration intravenously. The method...

Hormonal Control of Tyrosine Hydroxylase in the Median Eminence: Demonstration of a Central Role for the Pituitary Gland*

In intact male rats the concentration of dopamine in hypophysial portal plasma of animals treated simultaneously with estradiol and progesterone was twice that of animals treated with the solvent vehicle. Treatment with estradiol or progesterone alone had no effect on dopamine in portal plasma. The rate of synthesis of dihydroxyphenylalanine (DOPA), the precursor of dopamine, in tuberoinfundibular dopaminergic (TID) neurites in the median eminence (ME) was 15 +/- 1.0 (mean +/- SE) pmol DOPA/ME.h in estradiol-progesterone-treated animals compared to 3.2 +/- 0.02 in vehicle-treated controls. Treatment with estradiol or progesterone alone gave a result similar to that seen in controls. In hypophysectomized animals treated with estradiol and progesterone, DOPA synthesis in the ME was greatly attenuated compared to that in intact rats. The in situ activity of tyrosine hydroxylase (TH; expressed as moles of DOPA per mol TH/h) in the ME was 178 +/- 16.5 in estradiol-progesterone-treated intact rats, but was 27 +/- 2.4, 52 +/- 4.2, and 35 +/- 2.5 in animals treated with the solvent vehicle, estradiol, and progesterone, respectively. In hypophysectomized rats the in situ activity of TH in the ME of animals treated with estradiol and progesterone was 53 +/- 8.4, which was significantly (P less than 0.01) less than that in similarly treated intact animals. The circulating PRL level in vehicle-treated animals was 35 +/- 4.6 ng/ml compared to 121 +/- 16 in estradiol-treated animals and 133 +/- 12.2 in estradiol- and progesterone-treated rats, indicating that the difference in the effects of estradiol and estradiol-progesterone on dopamine release, DOPA synthesis, and in situ TH activity was not solely due to a difference in circulating PRL levels. Maintenance for 7 days of anterior pituitary tissue as a graft in a lateral ventricle of intact rats resulted in a 2-fold increase in the synthesis of DOPA and TH activity in the ME compared to that in animals with liver implants. Results obtained in hypophysectomized animals with implants were similar to those in intact animals. The concentrations of PRL in cerebrospinal fluid of intact rats and hypophysectomized rats with anterior pituitary implants in the lateral ventricles were 96 +/- 32 and 127 +/- 35 ng/ml, respectively, which was significantly (P less than 0.001) greater than those in animals with liver implants. We suggest that a factor of pituitary origin stimulates TH activity in TID neurons. This stimulation may be due to PRL, but the existence of another stimulatory substance secreted by pituitary cells cannot be excluded.

Concentrations of dopamine and noradrenaline in hypophysial portal blood in the sheep and the rat.

The concentrations of dopamine, noradrenaline and their respective primary neuronal metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethyleneglycol (DHPG) were measured in the hypophysial portal and peripheral plasma of sheep and rats by combined gas chromatography-mass spectrometry. Hypophysial portal and jugular blood samples were taken at 5- to 10-min intervals for 3-7 h from six conscious ovariectomized ewes. Blood was also collected for 30 min under urethane anaesthesia from the cut pituitary stalk from 16 pro-oestrous female and five intact male rats. In ovariectomized ewes, noradrenaline concentrations were higher in hypophysial portal plasma than in peripheral plasma (6.6 +/- 0.8 vs 2.2 +/- 0.4 nmol/l). In contrast, dopamine was undetectable (less than 1 nmol/l) in the portal and peripheral plasma of all ewes. Plasma levels of DOPAC and DHPG in portal and jugular samples were similar. In all pro-oestrous female rats, plasma concentrations of dopamine were higher in portal blood than in jugular blood (8.0 +/- 1.4 vs 4.8 +/- 0.6 nmol/l). Detectable concentrations of dopamine were measured in the portal plasma of two out of five male rats. Noradrenaline concentrations were higher in portal plasma than in peripheral plasma of both female (8.3 +/- 1.7 vs 3.7 +/- 0.6 nmol/l) and male (14.8 +/- 2.7 vs 6.1 +/- 1.2 nmol/l) rats. These data show that noradrenaline, but not dopamine, is secreted into the long portal vessels in sheep. The results suggest that there are species differences in the secretion of hypothalamic dopamine into hypophysial portal blood.

Plasma catecholamine concentrations in rainbow trout ( Salmo gairdneri) at rest and after anesthesia and surgery

The effects of surgery and anesthesia on concentrations of plasma epinephrine (E), norepinephrine (NE), and dopamine (DA) were investigated in rainbow trout fitted with dorsal aorta cannulae. Baseline catecholamines (CA) concentrations, established in resting rainbow trout, were 1.55 ± 0.90 ϱmol/ml ( X ± SD) for E, 2.07 ± 1.26 for NE, and 1.33 ± 0.87 for DA. These values were based on the pooled analyses of five individual fish taken over seven different sampling periods. The E:NE ratio in resting fish was always less than 1.0. In a second experiment, fish were subjected to dorsal aorta cannulation and sequential blood samples were taken immediately after surgery, and 6, 24, and 48 hr later. Plasma E concentrations were 36 times greater than baseline values in the first sample; NE was 15 times greater and DA was 41 times greater. After surgery, plasma concentrations of all CAs fell rapidly but values were still higher than baseline 6 hr after surgery, then were near baseline at 24 and 48 hr after surgery. The E:NE ratio was about 3.0 immediately after surgery, dropped to 1.8 at 6 hr, and was about 1.0 at 24 and 48 hr. In a third experiment, plasma CAs were determined in a group of five animals anesthetized with tricaine methanesulfonate (100 mg/ml) to advanced anesthesia, and then allowed to recover in flowing well water over a 12-hr observation period. Plasma E and NE concentrations in the fish during early anes-thesia (1.14 ± 0.14 min) were not significantly different from preanesthesia values. During advanced anesthesia (2.31 ± 0.21 min), values for E and NE were significantly greater and continued to be elevated during the 12-hr recovery period. The E:NE ratio exceeded 1.0 during advanced anesthesia and for the rest of the experiment.

The role of endogenous dopamine in congestive heart failure.

Although the effects of epinephrine and norepinephrine in congestive heart failure have been extensively studied, and exogenous dopamine, another of the catecholamines, has been widely used for the treatment of congestive heart failure, little attention has been paid to the physiological significance of endogenous dopamine in this condition. The present study was therefore designed to assess the physiological significance of endogenous dopamine in congestive heart failure. Nineteen patients with congestive heart failure caused by such conditions as acute myocardial infarction, valvular disease and dilated cardiomyopathy were examined before and after treatment with diuretics, digitalis and vasodilators. Electrolyte, creatinine and catecholamine concentrations in plasma and urine were analyzed. Urinary dopamine levels were increased in 13 out of 19 cases before treatment and returned to the normal range after treatment, falling from 2448 +/- 950.7 to 528.8 +/- 56.3 micrograms/day (normal level, less than 700 micrograms/day). Urinary dopamine excretion was markedly elevated within 24 hours after the onset of symptoms of heart failure, such as chest pain, palpitations and dyspnea. The relationship between urinary dopamine excretion and time after the onset of symptoms showed a strong statistical correlation (r = 0.55, p less than 0.001). Urinary dopamine excretion was also well correlated with plasma dopamine concentration, urinary norepinephrine excretion and venous pressure. From these results, it is concluded that endogenous dopamine seems to play an important role during the acute phase of congestive heart failure.

Efficacy of Ibopamine Treatment in Patients with Advanced Heart Failure

Eighteen patients with severe unstable heart failure who presented with hemodynamic deterioration after withdrawal of i.v. dopamine were treated with high doses of ibopamine (100 mg eight times a day, orally) in association with digitalis, diuretic, and vasodilator therapy. Ibopamine, used at these dosages, could effectively substitute for the i.v. infusion of dopamine in 15 of the 18 studied patients. Each patient was studied by right heart Swan-Ganz catheterization and two-dimensional echocardiography before and during ibopamine infusion, after dopamine withdrawal, and after acute ibopamine administration; measurements were then made after 3 months of chronic ibopamine treatment (100 mg eight times a day). Blood samples for plasma dopamine and epinine concentrations were obtained at the time of the hemodynamic measurements. Both drugs did not induce any significant change in arterial pressure whereas heart rate was slightly reduced after dopamine and chronic ibopamine. Cardiac index and stroke volume index were significantly increased by dopamine (from 1.81 to 2.24 L/ min/nr and from 20.3 ± 6.5 to 27.7 ± 8.1 ml/beat/m2) and acute and chronic ibopamine (from 1.80 to 2.15 and 2.23 L/min/nr and from 22.4 ± 6.8 to 28.2 ± 7.5 and 30.3 ± 7.0 ml/beat/nr. respectively); these changes were attended by a decrease in systemic vascular resistance: pulmonary pressures were not significantly modified. No significant change of the echocardiographic parameters was noted. During dopamine infusion, mean dopamine plasma concentrations were 211.8 ± 32.4 pmol/ml; after acute and repeated administration of ibopamine, free epinine plasma concentrations averaged 45.1 ± 14.5 and 62.2 ± 12.7 pmol/ml, respectively. Among the hematochemical parameters, plasma sodium concentration tended to decrease during chronic ibopamine and plasma creatinine was reduced by both dopamine and ibopamine. The New York Heart Association functional class significantly improved, averaging 3.9 before and 3.1 after chronic ibopamine. The survival rate, excluding four patients who underwent heart transplantation, was 71% at 6 months and 61% at 12 months. In conclusion, we think that frequent daily administrations of ibopamine can adequately substitute for i.v. dopamine; this therapeutic scheme can be used in patients awaiting cardiac transplantation.

Efficacy of Ibopamine Treatment in Patients with Advanced Heart Failure

Eighteen patients with severe unstable heart failure who presented with hemodynamic deterioration after withdrawal of i.v. dopamine were treated with high doses of ibopamine (100 mg eight times a day, orally) in association with digitalis, diuretic, and vasodilator therapy. Ibopamine, used at these dosages, could effectively substitute for the i.v. infusion of dopamine in 15 of the 18 studied patients. Each patient was studied by right heart Swan-Ganz catheterization and two-dimensional echocardiography before and during ibopamine infusion, after dopamine withdrawal, and after acute ibopamine administration; measurements were then made after 3 months of chronic ibopamine treatment (100 mg eight times a day). Blood samples for plasma dopamine and epinine concentrations were obtained at the time of the hemodynamic measurements. Both drugs did not induce any significant change in arterial pressure whereas heart rate was slightly reduced after dopamine and chronic ibopamine. Cardiac index and stroke volume index were significantly increased by dopamine (from 1.81 to 2.24 L/min/m2 and from 20.3 +/- 6.5 to 27.7 +/- 8.1 ml/beat/m2) and acute and chronic ibopamine (from 1.80 to 2.15 and 2.23 L/min/m2 and from 22.4 +/- 6.8 to 28.2 +/- 7.5 and 30.3 +/- 7.0 ml/beat/m2, respectively); these changes were attended by a decrease in systemic vascular resistance; pulmonary pressures were not significantly modified. No significant change of the echocardiographic parameters was noted. During dopamine infusion, mean dopamine plasma concentrations were 211.8 +/- 32.4 pmol/ml; after acute and repeated administration of ibopamine, free epinine plasma concentrations averaged 45.1 +/- 14.5 and 62.2 +/- 12.7 pmol/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability and Pharmacokinetics of Oral Dopamine in Dogs

AbstractThe bioavailability and pharmacokinetics of oral dopamine (DA) were studied in dogs. Plasma concentrations of DA and its main metabolites, such as dopamine-3O-sulfate (DA-SO4) and 3,4-dihydroxyphenyl acetic acid (DOPAC) were determined after intravenous or oral administration of DA using high-performance liquid chromatography with electrochemical detector (HPLC-ECD). Following the intravenous administration, plasma DA-SO4 and DOPAC concentrations were lower than the plasma DA concentration. On the other hand, following the oral administration, plasma DA-SO4 and DOPAC concentrations were much higher than the plasma DA concentration. The absolute bioavailability of DA after oral administration was calculated to be ~3%. Intraduodenal and mesenteric venous administration of DA revealed that DA-SO4 was mainly produced in the intestine and DOPAC was produced in the intestine and liver. On the basis of these observations, the bioavailability and pharmacokinetics of oral DA are discussed in connection with the metabolic inactivation due to first-pass metabolism.

Mass and in situ activity of tyrosine hydroxylase in the median eminence: effect of hyperprolactinemia.

The role of PRL in the control of catecholaminergic hypothalamic neurons of female rats was investigated. The in situ activity of tyrosine hydroxylase (TH) in neurites of these neurons was assayed by measuring the rate of accumulation of L-3,4-dihydroxyphenylalanine (DOPA) in the median eminence (ME) after the administration of a DOPA decarboxylase inhibitor. The mass of TH was measured by an immunoblot assay using rat TH as the standard. Hyperprolactinemia was induced by pituitaries implanted beneath a renal capsule. Hyperprolactinemia resulted in a significant increase in the in situ activity of TH without an increase in TH mass. The release of dopamine from hypothalamic neurons was assessed by measuring the concentration of dopamine in hypophysial portal plasma. The mean concentration of dopamine in portal plasma of rats bearing pituitary implants was 3 times that in controls. When circulating PRL was neutralized by administration of antiserum against rat PRL, the activity of TH was reduced significantly compared to that in animals treated with preimmune serum. In animals bearing pituitary implants, phosphorylation of TH in the ME was not different from that in control animals. We conclude that the biosynthetic and secretory activities of dopaminergic neurons of the hypothalamus are potentiated by PRL, but the potentiation is not due to an increase in the mass of TH or to the capacity of the neurites of the ME to phosphorylate TH.

Steady-state dopamine clearance in critically ill infants and children.

Little is known about dopamine pharmacokinetics in pediatric patients, especially in critically ill infants and children who often receive treatment with dopamine. Arterial plasma concentrations of dopamine were measured in 27 patients who were hemodynamically stable and received dopamine for at least one hour. The dopamine levels were measured using liquid chromatography with electrochemical detection. Dopamine clearance averaged 96.2 +/- 55.4 ml/kg.min in 13 patients in the neonatal ICU, and 58.8 +/- 51 ml/kg.min in 14 patients in the pediatric ICU. Six patients had renal (BUN greater than 25 mg/dl, or creatinine greater than 1.2 mg/dl) or hepatic (liver enzymes greater than 3 times normal) dysfunction. Dopamine clearance in these patients (25.1 +/- 17.2 ml/kg.min) was substantially lower than in the other patients (p less than .01). Neither postnatal nor gestational age correlated with dopamine clearance. Substantial interindividual variation was observed in steady-state dopamine clearance in critically ill infants and children, and plasma dopamine could not be predicted accurately from the dopamine infusion rate. Because of the more than three-fold prolongation of dopamine clearances in patients with hepatic or renal dysfunction, these patients may be more likely to suffer toxic effects of dopamine at the usual drug infusion rates.

Significance of serum thyrotropin and plasma dopamine concentration in the regulation of thyroid function in elderly subjects.

In our previous study, we observed a tendency towards an age-related increase in the serum thyrotropin (TSH) concentration. Regulatory mechanisms of TSH secretion in elderly subjects were studied. In 43 elderly subjects, serum TSH did not correlate significantly with serum T4, T3 free T4 or rT3. Further, those with increased TSH (greater than 5 mU/l, 9 subjects) did not overlap with those with low T3 (less than 0.92 nmol/1, 8 subjects). Increases in serum TSH were not associated with the presence of circulating anti-thyroid autoantibodies. A TRH test using a 500 micrograms single bolus injection was performed in 15 subjects. TSH response (basal: 1.92 +/- 1.42 (s.d.) mU/1, peak: 11.25 +/- 5.33 mU/1, sigma: 26.74 +/- 12.89 mU/1, respectively) did not differ significantly from that of younger subjects. T3 response after TRH varied greatly and a close correlation was observed between basal T3 and peak T3 (r = 0.86), and also between peak T3 and delta T3 (r = 0.81). A significant correlation was observed between sigma TSH and basal T3 (r = 0.60). Neither plasma cortisol, epinephrine nor norepinephrine concentrations showed any significant correlation with basal and TRH-stimulated TSH or T3 concentrations. However, the plasma dopamine concentration correlated significantly with sigma TSH (r = 0.60) and basal T3 (r = 0.52), respectively. In conclusion, the increase in serum TSH observed in elderly subjects was felt to represent a physiological adaptation to maintain serum T3. Low T3 subjects appear to have a disturbance in this mechanism, with decreased TSH and T3 response to TRH stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)