SUMMARYThe major protocol features of the immature rat uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used and the specificity of the assay for estrogens. It is concluded that three daily oral old rats, followed by determination of absolute uterus weights on the fourth day, provides a sensitive and toxicologically relevant in vivo estrogenicity assay. Rats are favoured over mice for reasons of toxicological practice, but the choice of test species is probably not a critical protocol variable, as evidenced by the similar sensitivity of rats and mice to the uterotrophic activity of methoxychlor. Vaginal opening is chemicals to reduce or abolish the uterotrophic response of estradiol is suggested to provide a useful extension of the uterotrophic assay foThe results of a series of studies on the environmental estrogen nonylphenol (NP), and its ng of the aliphatic sidechain is important for activity. 17 similar activity to estradiol in the uterotrophic assay, and is suggested to represent the 'parent' estrogen of NP. Benzoylation of r uterotrophic activity, in contrast to the enhancing effect of benzoylation on estradiol.Selected chemicals shown to be active in the immature rat uterotrophic assay were also evaluated in an in vitro yeast human estrogen receptor transactivation assay. Most of the chemicals gave similar qualitative responses to those seen in the uterotrophic assay, and the detection of the estrogen methoxychlor by the yeast assay evidenced a degree of intrinsic metabolic competence. However, the assay had a reduced ability (compared to rodents) to hydrolyse the benzoate ester of estradiol, and the estrogenic benzoate derivative of NP was not active in the yeast assay. These last results indicate that current metabolic deficiencies of in vitro estrogenicity assays will limit the value of negative data for the immediate future.The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and confirm the need for rigorous attention to experimental design and criteria for assessing estrogenic activity.3

This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.

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Summary1. The mechanism of efflux of (-)-[3H]-noradrenaline was examined in rabbit atria, which were pretreated with reserpine and pargyline. 2. Between 40 and 100 min, efflux occurred predominantly from a single intraneuronal compartment.3. Efflux was rapidy increased by (-)-and (+)-noradrenaline, tyramine and (±)-metaraminol, but not by (±)-isopropylnoradrenaline or (±)-normetanephrine. The increase in efflux produced by (-)-noradrenaline was inhibited by cocaine and desipramine but not by lidocaine. 4. Spontaneous effluxes, and those accelerated by (-)-noradrenaline, were temperature-sensitive. 5. Effiux was increased by ouabain, omission of K+, metabolic inhibition and lowering of the external Na± concentration. These effects were significantly reduced by cocaine and desipramine but not by lidocaine. 6. These findings provide evidence that the effiux of [3H]-noradrenaline from adrenergic nerves occurs by a cocaine-sensitive, carrier-mediated process. The characteristics of the efflux process are compatible with, but not conclusive proof for, the Na+-gradient hypothesis.

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