Acute alcohol effects on plasma estradiol levels in women

Acute administration of alcohol (0.695 g/kg) to healthy adult women resulted in peak blood alcohol levels between 70 and 75 mg/dl within 50–60 min after initiation of drinking. Alcohol induced a significant increase (x=18 pg/ml) in plasma estradiol levels (P<0.01). In contrast, after placebo ingestion, plasma estradiol levels did not change significantly. After alcohol intake, plasma estradiol levels reached peak values at 25 min following initiation of drinking when blood alcohol levels averaged 34 mg/ml. It is postulated that the alcohol-induced increase in plasma estradiol is due to changes in hepatic redox states associated with the catabolism of ethanol.     

Chronic ethanol intake modifies estrous cyclicity and alters prolactin and LH levels

The effect on the estrous cycle, as well as prolactin, luteinizing hormone (LH) and alcohol levels, were studied in female rats during chronic alcohol intake. Rats were fed the following diets for 5 weeks: a liquid ethanol diet (5% ethanol, w/v), an isocaloric liquid diet (pair-fed) or laboratory rat-chow and water ad lib. Ethanol-fed rats showed an irregular estrous cycle with a significant decrease in the frequency of the estrus + proestrus phases, and an increase in the duration of the diestrus + metaestrus phases, when compared with both the pair-fed and rat-chow groups. In these alcoholic rats, the estrous cycle phase was correlated with blood alcohol levels, which were found to be lower in the estrus + proestrus than in the other phases of the cycle. At the same time plasma prolactin levels were higher and plasma LH levels lower in the alcoholic rats than in either control group. These data indicate that chronic ethanol consumption prolongs the diestrus phase together with altered plasma prolactin and LH levels in female rats.     

Effect of acute ethanol ingestion on integrated plasma prolactin levels in normal men

Healthy male subjects ingested 1.0 g ethanol/kg (Alcohol Day) and caloric equivalents of sucrose (Control Day). Plasma prolactin was determined on samples collected at 20-min intervals by serial constant blood exfusion, from 2 hr before to 4 hr after the drink. In 14 of the 15 men studied, plasma prolactin levels during the 2-hr period after alcohol administration were elevated an average of 31% above values for the preceding 2-hr period. Data pooled for all subjects revealed a small but statistically significant increase in prolactin coinciding with ascending and peak concentrations of blood alcohol. A significant increment in prolactin was associated with peak blood alcohol levels when values were compared between control and alcohol treatment days. Although of statistical significance, these transient and variable increases were within the normal range of basal prolactin levels for most subjects and are unlikely to be physiologically meaningful.     

L-TYPE CALCIUM CHANNELS AND CRH-MEDIATED ACTH AND CORTISOL RELEASE IN HUMANS

1. The effect of pretreatment with nifedipine on naloxone-stimulated corticotrophin-releasing hormone (CRH)-induced adrenocorticotrophin (ACTH) release in humans was investigated. The mean peak plasma ACTH and cortisol levels and the mean peak change in cortisol levels from basal were significantly lower in the nifedipine/naloxone test than in the naloxone alone test. The integrated areas under the ACTH-time and cortisol-time curves were reduced by 33 and 49%, respectively, in the nifedipine/naloxone test compared with the naloxone alone test. These results correlate well with published in vitro studies. 2. Acute administration of oral nifedipine partially inhibited naloxone-stimulated ACTH and cortisol release, probably by blockade of plasma membrane voltage-dependent L-type calcium channels normally activated following binding of CRH to pituitary corticotroph receptors. 3. Naloxone-induced CRH release may replace insulin hypoglycaemia testing of pituitary ACTH reserve in humans.     

Participation of the opioid system in the regulation of prolactin secretion in androgenized rats: effect of ovarian steroids.

We examined the role of the opioid system on the regulation of prolactin secretion in neonatally androgenized rats and evaluated the participation of ovarian steroids in this regulation. Androgenized rats exhibited an increase of prolactin secretion with higher serum circulating levels in the afternoon (1800) than in the morning (1000). The administration of the opioid antagonist naloxone (2 mg/kg, 30 min before decapitation) reduced serum prolactin levels in both groups. To identify the opioid receptor subtypes involved in this regulation, opioid agonists were administered i.c.v. 15 min before the decapitation (1000). The mu-opioid receptor agonist DAMGO ([D-Ala2, NMe-Phe4, Gly5-ol]-enkephalin) caused a significant increase in serum prolactin concentration. The selective kappa-opioid receptor agonist U-50, 488H (trans-(+/-)-3,4-dichloro-N-[2(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methane sulfonate salt) induced a small but significant increase in serum prolactin levels but no effect was observed after administration of the delta-opioid agonist DPDPE ([D-Pen2, D-Pen5]-enkephalin). The role of oestradiol and the opioid system in the continuous secretion of prolactin was also study. Chronic gonadectomy (3-4 weeks) reduced serum prolactin concentrations measured at 1000 but the administration of naloxone had no effect. Three days of oestrogen treatment (2 microg/rat in oil) restored serum prolactin levels compared with ovariectomized animals and this effect was abolished by naloxone treatment. Interestingly, acute ovariectomy or administration of tamoxifen to intact androgenized rats did not prevent the continuous secretion of prolactin observed in these animals and naloxone treatment reduced serum prolactin levels in both groups of rats. We also examine the participation of adrenal progesterone and the endogenous opioid peptides on the regulation of prolactin levels in androgenized rats. After adrenalectomy, no changes in serum prolactin levels (1000) were observed compared with the control animal and naloxone treatment significantly reduced circulating prolactin levels. Progesterone treatment to intact androgenized rats significantly increased prolactin levels and the administration of naloxone blocked the stimulatory effect of the steroid. These results suggest that the opioid system play a role in the regulation of prolactin secretion in androgenized rats modulated by the persistence of oestrogen action. Moreover, the presence or absence of progesterone did not modify the regulation of prolactin secretion by the opioids. The mu- and kappa-opioid receptor subtypes are the ones involved in the modulation of pituitary prolactin secretion.     

Hypothalamic–pituitary–adrenal axis and ethanol modulation of deoxycorticosterone levels in cynomolgus monkeys

Rationale The metabolites of deoxycorticosterone (DOC) and progesterone, allotetrahydrodeoxycorticosterone and allopregnanolone, are potent endogenous neuroactive steroids that are increased in rodent brain and plasma after hypothalamic–pituitary–adrenal (HPA) axis activation by acute stress or ethanol administration. However, little data are available for male nonhuman primates.Objective To determine DOC concentrations in plasma samples from 11 monkeys following challenge of the HPA axis with naloxone, corticotropin-releasing factor (CRF), dexamethasone, adrenocorticotropic hormone (ACTH) following dexamethasone pretreatment and ethanol.Methods DOC levels were measured in monkey plasma by radioimmunoassay.Results DOC levels were increased after naloxone (125 μg/kg and 375 μg/kg, respectively) and CRF administration (1 μg/kg), and decreased following dexamethasone (130 μg/kg) administration. ACTH (10 ng/kg) challenge, 4–6 h after 0.5 mg/kg dexamethasone, and administration of ethanol (1.0 g/kg and 1.5 g/kg) had no effect on DOC concentrations. DOC levels were positively correlated with cortisol and ACTH levels after the naloxone (375 μg/kg), CRF, and ACTH challenges. Finally, the suppression of DOC levels measured after dexamethasone was negatively correlated with subsequent alcohol self-administration.Conclusions These results suggest that DOC levels in monkeys are regulated by the HPA axis and may contribute to physiological responses following activation.     

Blockage of progesterone-induced release of luteinizing hormone and prolactin byd-amphetamine and fenfluramine in rats

Subcutaneous administration ofd-amphetamine at various doses (1.25, 2.5, and 5 mg/kg) decreased plasma luteinizing-hormone levels in ovariectomized rats primed with estradiol and injected with progesterone. In these animals prolactin levels decreased after injection of 0.6 and 1.25 mg/kg ofd-amphetamine. No significant hormone modifications were detected in ovariectomized and ovariectomized estradiol-primed rats after injection of 2.5 mg/kg ofd-amphetamine. Fenfluramine at doses of 25 mg/kg induced decreases of plasma LH and prolactin levels in ovariectomized estradiol-and progesterone-treated rats. A low dose of fenfluramine, 2.5 mg/kg, had no effect.It is concluded thatd-amphetamine and fenfluramine are able to alter the facilitatory actions of progesterone on luteinizing hormone and prolactin release in ovariectomized estradiol-primed rats.National Scientific Research Council of Argentina (CONICET) investigator     

Naloxone suppresses buprenorphine stimulation of plasma prolactin

The effects of parenterally-administered buprenorphine and simultaneous injection of naloxone was evaluated in six healthy adult males. Each subject was studied on six occasions, an average of 10 days apart, and received either two simultaneous intramuscular injections of saline, buprenorphine 0.3 mg and saline, or buprenorphine 0.3 mg and 0.6 mg, 0.45 mg, 0.3 mg, or 0.15 mg of naloxone. Simultaneous injection of buprenorphine 0.3 mg and saline resulted in an average increase in plasma prolactin above baseline levels of approximately 10 and 25 ng/ml, 30 and 55 minutes after injection. Buprenorphine-induced stimulation of plasma prolactin levels was statistically significantly greater than basal prolactin values (p less than 0.01). When 0.6 mg of naloxone was simultaneously injected with 0.3 mg buprenorphine, peak plasma prolactin levels were significantly lower (p less than 0.05) than prolactin values after administration of 0.3 mg buprenorphine and saline. Simultaneous injection of 0.45 mg naloxone and 0.3 mg buprenorphine also resulted in a significant attenuation (p less than 0.05) of buprenorphine-stimulated prolactin levels. Injection of 0.3 mg or 0.15 mg of naloxone did not inhibit prolactin stimulation produced by buprenorphine 0.3 mg. These findings demonstrate a dose-effect relationship between naloxone concentration and suppression of the increase in plasma prolactin levels produced by administration of buprenorphine 0.3 mg. As prolactin stimulation occurs shortly after opioid agonist administration and is temporally concordant with the rapid induction of pharmacologic reinforcement associated with opiate abuse, naloxone added to buprenorphine parenteral preparations may reduce the abuse potential of buprenorphine.     

Alcohol effects on plasma luteinizing hormone levels in menopausal women

Plasma luteinizing hormone (LH) levels were determined in five healthy post-menopausal adult females prior to, during, and following a period of acute alcohol intoxication. LH levels were also determined in the same women following acute administration of a nonalcoholic beverage which had identical isocaloric value of alcohol. Plasma samples were collected at 30-minute intervals from an indwelling intravenous catheter from 120 minutes prior to alcohol or isocaloric beverage administration to 300 minutes following beverage intake. All women became moderately intoxicated after acute alcohol administration and developed peak blood alcohol levels of 94 mg per dl between 60 to 90 minutes following alcohol intake. LH levels determined before administration of alcohol or isocaloric beverage were not significantly different and were within the range of normal values for healthy, post-menopausal women. No significant differences were found between LH levels following alcohol administration when compared with LH values after isocaloric beverage. These data indicate that acute alcohol intake which produces blood alcohol levels slightly below usual legal limits of intoxication does not suppress LH in post-menopausal females. Since post-menopausal females do not have significant estradiol feedback control of LH secretory activity, and since LH secretory activity in post-menopausal women (in contrast to pre-menopausal females) is more sensitive to the inhibitory actions of drugs which may affect adrenergic and dopaminergic pathways in brain, the findings obtained in this study do not support an acute alcohol effect upon hypothalamic-pituitary modulation of gonadotrophin release in humans.     

Further evidence for effects of ethanol on gonadotrophins and prolactin secretion in female rats

The effect of different doses of ethanol (0.5, 1.0, 2.0 and 4.0 g/kg) on LH, FSH and prolactin levels has been studied in female rats. Ethanol was administered in preovulatory periods (18 hr of diestrous or 9 hr of proestrous) and hormonal levels were measured at the 18 hr of proestrous. Ethanol administered at the 18 hr of diestrous produces a biphasic effect on serum LH levels. High doses of alcohol significantly decreased LH levels, whereas low doses (0.5 g/kg) increased the hormonal levels. When ethanol-treatment was at the 9 hr of proestrous, it only decreased LH levels with the dose of 4.0 g/kg. Serum FSH levels were unaffected by the preovulatory administration of ethanol. Serum prolactin concentrations were significantly elevated after i.p. administration of ethanol at the 18 hr of diestrous and the 9 hr of proestrous. The hyperprolactinemia is more pronounced in the rats treated at the 9 hr of proestrous. The results of these studies suggest that the ability of ethanol to modify LH and prolactin levels is due to a central depression caused for alcohol. These effects of ethanol could be mediated by the hypothalamic releasing factors and/or could be due to a direct action on the pituitary function. The sum of these effects produces important failures of the reproductive function in the female rat.     

Cocaine and alcohol interactions in the rat: effect on cocaine pharmacokinetics and pharmacodynamics

The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration-time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 +/- 0.044 to 0. 754 +/- 0.071. Also, the absorption rate constant increased from 0. 199 +/- 0.045 to 0.276 +/- 0.059 min-1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 +/- 3.6 to 40.0 +/- 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration-neurochemical effect relationship by the sigmoid-Emax pharmacodynamic model showed that Emax increased from 850 +/- 200 to 1550 +/- 640% of baseline due to alcohol coadministration, whereas EC50 decreased from 3400 +/- 580 to 2000 +/- 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharmacodynamic model used to examine the plasma cocaine concentration-change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coadministration also potentiates the neurochemical response to cocaine administration.     

Plasma pregnenolone levels in cynomolgus monkeys following pharmacological challenges of the hypothalamic-pituitary-adrenal axis

Pregnenolone (PREG) is an endogenous neuroactive steroid that is increased in rodent brain and plasma after hypothalamic-pituitary-adrenal (HPA) activation by acute stress or ethanol administration. Plasma levels of PREG metabolites are altered by pharmacological challenges of the HPA axis, however little is known about HPA regulation of PREG levels in monkeys. PREG concentrations were determined by radioimmunoassay in plasma samples from cynomolgus monkeys, following challenge with naloxone (125 and 375 microg/kg), corticotropin-releasing factor (CRF; 1 microg/kg), dexamethasone (130 microg/kg), adrenocorticotropic hormone (ACTH; 10 ng/kg; 4-6 h after 0.5 mg/kg dexamethasone) and ethanol (1.0 and 1.5 g/kg). Naloxone increased PREG levels, while CRF appeared to increase metabolism of PREG to deoxycorticosterone (DOC). ACTH, administered after dexamethasone, reduced PREG levels, despite an increase in plasma cortisol. Ethanol did not alter PREG levels. Changes in PREG levels were correlated with changes in DOC levels after naloxone 125 microg/kg, CRF, ethanol 1.5 g/kg, and dexamethasone challenges. Furthermore, dexamethasone-induced changes in PREG levels were correlated with subsequent alcohol intake. These data suggest that PREG responses to dexamethasone challenge may represent a trait marker of alcohol drinking. The lack of effect of ethanol on PREG levels suggests differential regulation in non-human primates vs. rodents.     

酒精依赖大鼠戒断行为与血浆ACTH、皮质醇含量变化的观察

目的·· :研究慢性酒精刺激和戒断大鼠血浆促肾上腺皮质激素(ACTH)、皮质醇与其相关行为变化的关系 ,同时观察纳洛酮翻转作用。方法·· :给大鼠自由饮酒28d ,观察对照组、饮酒组及纳洛酮治疗组的戒断症状、游泳时间 ;利用放射免疫分析法检测血浆中ACTH、皮质醇水平。结果·· :饮酒组戒断2 -48h戒断症状评分均明显比对照组高,以戒断6h评分最高(16.5±s3.12,P<0.01),其游泳时间在戒断6h为22.8min±s4.2min ,与对照组比显著延长(P<0.01) ;饮酒28d及戒断后血浆皮质醇水平渐升高,在戒断6h达最高(17.03ng·ml-1±s3.9ng·ml-1) ,至72h时降至正常水平 ;而血浆ACTH水平在饮酒28d及戒断后4h、24h显著降低 ,48h、72h逐渐恢复正常水平。纳洛酮治疗组与饮酒组比 ,戒断症状评分明显降低 ,游泳时间显著缩短 ,血浆皮质醇水平亦明显降低 ;但ACTH水平与饮酒组比较无显著性差异。结论·· :慢性酒精刺激及戒断导致垂体 -肾上腺轴功能紊乱 ,纳洛酮能阻止皮质醇的升高 ,减轻酒精戒断症状。     

Reduced estradiol production by a substituted triazole results in delayed ovulation in rats

Ovulation in the rat is delayed by a single administration of the substituted triazole R151885 (1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol). This delay results from a 24-hr shift in the preovulatory luteinizing hormone (LH) surge since administration of chorionic gonadotrophin on proestrus restores ovulation. Plasma levels of estradiol are markedly reduced (42-45%) 6-12 hr after administration of R151885. The restoration of ovulation in R151885-pretreated rats, by administration of exogenous estradiol benzoate, indicates that the reduced estradiol levels play a pivotal role in the delay of ovulation. Granulosa cells isolated from rat ovaries produce estradiol and progesterone in vitro in the presence of both follicle-stimulating hormone and testosterone. The addition of R151885 to such cultures results in a dose-dependent inhibition of estradiol production (69% by 1 microM) without a significant effect on progesterone production. This inhibition occurs at concentrations of R151885 similar to those measured in vivo. R151885 is a competitive inhibitor of human placental aromatase (apparent Ki with androstenedione substrate of 410 nM) and produces a type II spectral perturbation of cytochrome P-450 from placental microsomes. Pituitaries isolated from R151885-treated rats have reduced LH output in response to gonadotrophin-releasing hormone stimulation compared with those of controls. It is proposed that R151885 competitively inhibits aromatase activity in developing ovarian follicles. The resultant temporary reduction of plasma estradiol levels at a critical time in the estrous cycle, and consequent inadequate pituitary sensitization, produces a 24-hr delay in the preovulatory LH surge and hence ovulation is delayed by 24 hr.     

The effects of cocaine on gonadal steroid hormones and LH in male and female rhesus monkeys.

Cocaine stimulates significant increases in estradiol, testosterone (T), and luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between the gonadal steroid hormones and LH have not been determined. The effects of i.v. cocaine (0.8 mg/kg) or saline placebo administration on estradiol, T, and LH were compared in follicular phase female and male rhesus monkeys. Samples for hormone analysis were collected at 2-min intervals for 20 min, then at 10-min intervals for 50 min. Peak plasma cocaine levels were detected at 4 min and pharmacokinetic analyses showed no significant gender differences. Baseline hormone levels were equivalent before saline and cocaine administration, and saline did not alter LH or estradiol levels. In females, when baseline estradiol levels were low (< 100 pg/ml), LH increased significantly within 8 min after cocaine administration (P < 0.05), but when baseline estradiol levels were high (> 100 pg/ml), LH levels did not change significantly after cocaine administration. Estradiol and T increased significantly after LH, within 16 min after cocaine administration (P < 0.01-0.001). In males, significant LH increases were detected at 16 min after cocaine administration (P < 0.05-0.001), but estradiol and T did not change significantly. Thus, cocaine may stimulate significant increases in estradiol and T in females but not in males. These rapid hormonal changes may contribute to cocaine's abuse-related effects, as well as to disruptions of the menstrual cycle during chronic cocaine administration.     

Possible role of prolactin in the induction of hypogonadism by chronic alcohol treatment in the male rat

Treatment of adult male rats with ethanol for a period of six weeks resulted in a numerical but not significant increase in plasma prolactin levels together with a reduction in plasma luteinizing hormone (LH) levels. Although basal plasma testosterone (T) levels were not affected in ethanol-treated animals, testicular weight was reduced and seminiferous tubules exhibited signs of atrophy. The responses of LH to luteinizing hormone releasing hormone (LHRH) and T to hCG were significantly impaired in ethanol-treated rats (p less than 0.01). Treatment with bromocriptine (1 mg/kg body weight/day), resulted in the expected decrease in plasma levels of prolactin and an increase in basal plasma LH levels to the levels found in control groups. Basal plasma T levels were not affected by bromocriptine. However, both plasma LH responses to LHRH and plasma T responses to hCG were significantly improved by bromocriptine treatment in alcoholic rats and became similar to the responses measured in control animals. The results suggest that bromocriptine-induced suppression of prolactin release has a beneficial effect on ethanol-induced hypogonadism.     

Lack of acute alcohol effects on estradiol and luteinizing hormone in female macaque monkey

The effects of alcohol (1.5, 2.5, 3.5 g/kg) on 17-β estradiol and LH were evaluated in adult female Macaque monkeys. Integrated plasma samples were collected prior to and following nasogastric intubation of alcohol or isocaloric sucrose control solutions. Samples were collected at 30 minute intervals over 240 minutes. Each alcohol dose and control was studied at menstruation, the peri-ovulatory and mid-luteal periods and the premenstruum. After low, moderate and high doses of alcohol, blood alcohol levels (BAL) averaged 140, 260 and 344 mg/dl at the peak of the ascending BAL curve. Despite high blood alcohol levels, there was no evidence of alcohol dose-related suppression of LH or 17-β estradiol at any phase of the menstrual cycle. These data are consistent with our findings in human females that acute alcohol intoxication did not suppress LH or estradiol. The apparent resiliency of human and Macaque females to acute alcohol effects on reproductive hormones contrasts sharply with data obtained in males that alcohol significantly suppresses testosterone in all species studied.     

Possible prolactin-mediated effects of melatonin on gonadotropin secretion in the rat

Melatonin administration to pituitary-grafted male and female rats resulted in a marked decrease of previously high plasma prolactin levels, while an increase in prolactin levels was observed in sham-operated controls. The latter effect was significant only in males. Treatment with melatonin did not modify basal LH hormone levels or LH responses to luteinizing hormone-releasing hormone (LHRH) in sham-operated rats of either sex. However, in pituitary-grafted females, melatonin increased both basal and LHRH-stimulated LH levels towards values recorded in sham-operated controls. No effects on basal LH levels were detected in grafted males under melatonin treatment, but the response of LH to LHRH was markedly increased and no longer differed from the values measured in sham-operated control animals pretreated with saline. Melatonin did not affect follicle stimulating hormone (FSH) levels except for an increase in FSH response to LHRH in grafted females. These findings suggest the existence of sex-dependent effects of melatonin on LH and FSH secretions. These effects of melatonin may be mediated by the different plasma prolactin levels in pituitary-grafted and sham-operated rats.     

Studies on metabolism and effects of estrogen on pituitary prolactin and LH secretion.

The effect of a subcutaneous injection of estradiol on the secretion of pituitary prolactin in the rat and the relationship between serum estradiol level and luteinizing hormone (LH) secretion in mare were reviewed. In addition, the effect of estradiol injection on LH secretion and the metabolism of [14C] estradiol in intact and bile duct fistulated pony mares were studied. Low (0.1 mug/day/rat) to moderate dose (5 mug/day/rat) of estradiol benzoate injected subcutaneously to mature or immature rats significantly increased pituitary content of prolactin and serum prolactin level five- to tenfold. On the other hand, high dose of estradiol (10 mug/day/rat or more) was less effective in stimulating prolactin secretion, and it appeared that progesterone injected concurrently with estradiol had some inhibitory action on the stimulatory effect of estradiol. Studies in pony mares showed that the physiologic level of serum estradiol during proestrus was important for the induction of the ovulatory surge of LH. Intramuscular injection of a low dose (2 or 4 mg/mare) of estradiol was stimulatory, whereas a high dose (8 mg/mare) was inhibitory for LH secretion in pony mares. Results of the estradiol metabolism studies indicated a relatively long half-life for estradiol in the mare. The majority of the [14C] estradiol metabolites appeared in the urine within 24 hr following intravenous injection. Enterohepatic circulation appeared to be important for estradiol metabolism in mare.     

Pharmacokinetic and concentration-effect studies with intravenous metoclopramide.

1 Pharmacokinetic and concentration-effect studies have been carried out following intravenous injection of 10 mg metoclopramide hydrochloride to seven normal male volunteers. 2 It is proposed that a two-compartment model adequately describes the disposition of the drug which is rapidly distributed (T1/2alpha = 4.9 +/- 1.1 min) and eliminated (T1/2beta = 165.7 +/- 20.2 min). Total body plasma clearance of the drug is high (10.9 +/- 1.5 ml min-1 kg-1) and approximates to liver plasma flow. 3 Metoclopramide i.v. increases gastric emptying as measured by an ethanol absorption test (P less than 0.005). The duration of this effect is at least 3 h. 4 Ethanol given after i.v. metoclopramide administration produces significant sedation during the first hour and at 3 h (P less than 0.001). 5 The effect of metoclopramide on gastric emptying, and the degree of sedation induced by ethanol would appear to be related to plasma metoclopramide concentration. 6 Metoclopramide increases serum prolactin to 59 +/- 5.8 microgram/1 at 30 min after injection. There is a linear relationship (r = 0.809) between serum prolactin increase and plasma metoclopramide concentration.