Search

We examined the effect of prenatal stress exposure on sensitivity to caffeine using behavioral and physiological measures. Pregnant rat were handled 5 minutes daily from the 14th to 21st day of gestation. Male offspring were tested when 60 days of age in a modified open field apparatus 30 and 90 minutes after injection with caffeine (0, 10, 30 mg/kg). Caffeine increased crossover frequency and duration at the 10 mg/kg dose. Rearing frequency and duration were increased by the 10 mg/kg dose while the 30 mg/kg dose was ineffective. Gnawing was increased by caffeine, especially 90 minutes postinjection. Headpoke activity was decreased by caffeine treatment. Caffeine had no effect on defecation and urination. Gnawing activity was increased by caffeine in prenatally nonstressed animals, but was depressed in prenatally stressed animals. Prenatal stress increased sensitivity to caffeine on corner activity and rearing. The other measures were not affected differentially by prenatal stress exposure. Rectal temperature was depressed 0.75°C in both prenatally stressed and nonstressed animals, by the 30 mg/kg dose of caffeine. Thus, our results indicate that prenatal stress affects sensitivity to caffeine in the adult offspring. However, the long-term effects of prenatal stress exposure are dependent on the measures employed.

Labeled medazepam (7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-diazepine-5-14C) and metabolites were identified and measured by two-dimensional thin-layer chromatography. In the dog, 2 mg/kg of medazepam-5-14C HCl given orally or i.v. did not yield measurable blood levels of intact drug. The close agreement of the amount of 14C excreted in the urine after oral and i.v. administration and of the rates of this excretion indicated that the labeled compound was well absorbed. Fractionation of the blood revealed that biotransformation of medazepam was a rapid process. After a higher dose, 20 mg/kg i.v., medazepam disappeared from the blood bi-exponentially with half-lives of 0.16 and 2.7 hr. Pathways of medazepam metabolism, which apparently did not include diazepam as an intermediate, were postulated on the basis of metabolites identified in experiments both in vivo and in vitro. In the rat, highest tissue concentrations of14C were seen 2–4 hr after an oral dose of 14C-medazepam HCl. It was clear from the metabolites identified that the formation of diazepam and phenolic diazepam metabolites represented an important pathway of medazepam metabolism in this species. The labeled compound was rapidly absorbed by two human subjects who received single 30-mg oral doses. The peak blood levels of medazepam (less than 0.2 μg/ml at 1–2 hr) declined rapidly with a half-life of 1–2 hr. A marked difference between the subjects in rates of elimination of metabolites from the blood and in excretion of urinary metabolites appeared related to body weight and the activity of drug-metabolizing enzymes. Preliminary evidence for diazepam formation in man was also obtained.

A correlation between the duration of the anticonvulsant activity of diaze- pam [7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (Ro 5-2807)] and the physiological disposition of the intact drug and three metabolites—(1) the N -demethylated derivative [7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (Ro 5-2180)], (2) the hydroxylated derivative [7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one (Ro 5-5345)], and (3) oxazepam [7-chloro-1 ,3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzodiazepin-2-one (Ro 5-6789)]—in mice is presented. Maximal protection for 6 hr against a standard 125 mg/kg s.c. convulsant dose of metrazol was afforded by a single 2.5 mg/kg oral dose of diazepam. Quantitative 3 H distribution after the oral administration of a single 2.5 mg/kg dose of diazepam- 3 H shows rapid absorption and a rapid increase over 1–30 min in the tissue-to-blood 3 H ratios of the brain, muscle, heart, fat and carcass. These ratios thereafter increase gradually or remain constant to 4 hr after drug administration. A 125 mg/kg s.c. injection of metrazol given 30 min after the oral administration of diazepam does not significantly affect the tissue-to-blood 3 H ratios nor does it alter the 3 H disposition, except between 4 and 6 hr, during which time a definite increase in the total 3 H concentration of the blood, brain and muscle is observed. This increase is reflected in an increase in the concentration of the parent compound and of the products of its hydroxylation and desmethylation in blood, brain and muscle. Differential analyses of blood, brain and muscle tissue samples for diazepam and three of its major metabolites (Ro 5-2180, Ro 5-5345 and Ro 5-6789) from 30 min to 24 hr show that, although the concentration of each component at 30 min is similar both in the absence and presence of metrazol, a definite shift in the slope of the fall-off patterns toward a slower rate of disappearance of the parent compound and of its hydroxylated and desmethylated derivatives is evident when the administration of diazepam is followed by a subcutaneous injection of metrazol. The major constituent in all three tissues, both in the absence and presence of metrazol, is the end product of metabolism, namely oxazepam (Ro 5-6789). Besides being present in much higher concentrations, unlike the parent compound and the other metabolites, Ro 5-6789 maintains a fairly constant level in all three tissues from 30 min to 12 hr and then gradually falls to 24 hr. Although the contribution of the parent compound and its hydroxylated derivative to the duration and degree of protection cannot be accurately defined, it appears that the degree of protection to the convulsant action of metrazol is most closely related to the rate of disappearance of the N -desmethyl derivative.

The rate and extent of levodopa absorption and excretion following intravenous and oral administration of 2− 14 Clevodopa to acute and chronically treated dogs were investigated. Plasma levels of intact levodopa following the intravenous administration declined rapidly during the first 4-6 hr. The elimination-rate constant of intact levodopa from the plasma ranged between 0.73 and 0.99 hr. −1 , which corresponds to a half-life of approximately 40-60 min. The elimination-rate constant of total plasma 14 C ranged between 0.007 and 0.085 hr. −1 , which corresponds to a half-life of 8-9 hr., indicating that the total 14 C was eliminated at one-tenth the rate of intact levodopa. Peak plasma levels of intact levodopa and of total plasma 14 C following oral administration were attained 25-30 min. after dosing. Approximately 70-75% of the intravenous and 57-70% of the oral radioactive doses were excreted in urine over a 72-hr. period. Levodopa and dopamine accounted for a very small percentage of the radioactivity in the urine. Approximately 3.0-7.0% of the intravenous or oral radioactive dose was excreted in the feces. The efficiency of absorption of total radioactivity was calculated to range between 83.0 and 92.0%. Analysis of the ratio of intact levodopa levels to total 14 C levels indicated that only 22.0-30.0% of the administered dose reached the general circulation as intact levodopa, suggesting that the remainder of the absorbed dose, approximately 60.0%, is biotransformed in the gastrointestinal tract prior to absorption and/or in the liver during its "first passage" to the general circulation.

We have examined factors that alter the effect of diazepam (DZ) on plasma corticosterone (CS) in rats. DZ had a biphasic effect on plasma CS levels: CS decreased with doses below 5 mg/kg and increased with higher doses. Peak response occurred 90 minutes post injection in both sexes. Plasma DZ levels were significantly higher in females than in males and peak at 10 and 30 minutes post injection in males and females, respectively. There was also a sex difference in the pattern of DZ metabolites. An acute stressor (30 minutes of immobilization) did not affect plasma CS levels in rats injected with a 5 mg/kg dose of DZ. Prenatally stressed animals did not differ in basal CS levels or in their response to 5 mg/kg of DZ compared to prenatally non-stressed animals. These two groups of animals also did not differ in plasma levels of DZ or of its metabolites. By contrast, the 5 mg/kg dose of DZ had no effect on plasma testosterone levels in control animals, but increased it in prenatally stressed animals. Furthermore, compared to non-stressed controls, prenatally stressed animals had lower baseline plasma testosterone levels. These results indicate that the effect of DZ on plasma CS is influenced by endogenous as well as exogenous factors and that these effects vary with the particular biochemical parameter under examination.

1. Blood levels and tissue distribution of chlordiazepoxide and its major metabolites have been correlated with observed changes in ‘aggression” and ‘activity” following oral administration of the compound to cynomolgus (Macaca fascicularis) primates.2. Distribution of 14C after a single oral dose of [2-14C] chlordiazepoxide (5 mg/kg) is indicative of rapid absorption, approximately 30% and 80% dose being absorbed by 0.25 h and 2 h respectively. Highest blood concentrations are observed 2-6 h after dosing. The relatively high content of 14C in the tissues and the corresponding low content in urine and faeces at 2-12 h after dosing are suggestive of tissue storage and/or enterohepatic recirculation.3. Analysis of blood, brain and muscle for chlordiazepoxide and its major metabolites indicate that these are present 0.25 h after dosing. Chlordiazepoxide and its N-desmethylated derivative reach peak concentrations in all three tissues 2 h after dosing while the peak for ‘lactam” is attained at 6 h. In all 3 t...

The duration of the anticonvulsant (antimetrazol) activity of chlordiazepoxide in mice in relation to blood levels and tissue distribution patterns of the parent drug and its major metabolites is presented. Quantitation of the effect of a 125 mg/kg s.c. injection of metrazol and the degree of protection by a single 20 mg/kg oral dose of chlordiazepoxide, based on measuring the incidence of defined seizure reactions, indicated maximal protection for 4 hr after chlordiazepoxide administration. The quantitative 14C distribution after the oral administration of a single 20 mg/kg dose of chlordiazepoxide-2-14C is indicative of a rapid absorption onset as well as of a gradual increase in the tissue-to-blood 14C ratios from 0.5 to 6 hr after administration. In contrast, a 125 mg/kg subcutaneous injection of metrazol given 30 min after the oral administration of chlordiazepoxide appears both to reduce markedly the rate of absorption and to alter the disposition of chlordiazepoxide. This alteration includes a reduction in the blood 14C and tissue 14C levels immediately after metrazol injection to 4 hr after chlordiazepoxide administration. Although the initial tissue-to-blood 14C ratios are similar to those seen in the absence of metrazol, they do not show the marked increment with time. Differential spectrofluorometric analyses of blood, brain and muscle tissue samples for chlordiazepoxide and its major metabolites show that N-desmethylchlordiazepoxide is the major constituent in all three tissues both in the absence and in the presence of metrazol. Besides being present in much higher concentrations, unlike the parent compound and other metabolites, the N-desmethyl derivative maintains a maximum level from 30 min to 4 hr in the brain and from 30 min to 6 hr in blood and muscle. Correlation of the levels of chlordiazepoxide and its metabolites in these tissues to its anticonvulsant (antimetrazol) activity indicates that it is the concentration of the N-desmethyl metabolite that most closely parallels the pattern of this anticonvulsant activity.

1. Changes in ‘aggression’ and ‘activity’ observed in cynomolgus primates (Macaca fascicularis) following administration of a single 2·5 mg/kg oral dose of diazepam have been related to blood levels and tissue distribution of the parent compound and its major metabolites.2. Distribution of 14C after a single oral dose of [2-14C]diazepam shows rapid absorption, 75% of the dose being absorbed by 2 h at which time highest blood concn. are observed. With the exception of muscle and carcass, tissue-to-blood ratios exceed 1·0 throughout 24 h. High 14C content in excreta between 2 and 12 h after dosing suggests hepatic recycling and/or tissue storage.3. Analyses of blood, brain and muscle from 0·25 to 24 h after dosing show the presence of diazepam and its major metabolites as early as 0·25 h after dosing, the N-desmethyl derivative predominating throughout the 24 h period. The concn. of diazepam in all three tissues falls relatively faster than its metabolites.4. Max. reduction in ‘aggression’ (79%) and...