No abstract

1 The absorption, excretion, distribution and metabolism of a new antidepressant agent, nomifensine, was examined in rats, dogs and monkevs. After oral administration ot '4C-nomifensine 1 mg/kg body weight, the compound was absorbed rapidly, and as shown in rats and dogs, virtually completely. Nomifensine was predominantly found in a conjugated form in the plasma of rats, dogs and monkeys. Nomifensine was bound to serum proteins (approximately 60%) and the degree of binding was not species specific. 2 The maximum levels of total radioactivity (unchanged drug and metabolites) in the blood were 0.50 + 0.14 gg equiv./ml (n= 5) in dogs and 0.34 + 0.17 jg equiv./ml (n = 6) in monkeys. These leves were markedly higher than those in rats, with values of 0.034 ± 0.014 gg equiv./ml at 0.5-0.75 h and 0.048 + 0.018 jLg equiv./ml at 2-8 h after dosing (second peak; n= 19). 3 The ratio of radioactivity in organs and tissues relative to plasma was small and similar to that in blood. The highest concentrations of radioactivity were measured in the excretory organs; the lowest concentrations were found in the brain. When multiple doses of '4C-nomifensine were administered accumulation was minimal. 4 After single oral doses, the plasma levels of radioactivity were higher than those of blood.Accumulation of unconjugated nomifensine in plasma could not be demonstrated in dog, and multiple doses of the drug had no influence on the elimination of either conjugated or unconjugated nomifensine. 5 Rats excreted about 50%and dogs excreted about 70% of the compound in urine, predominantly as conjugates. The metabolites found in man were also found in monkey, these being 4'-hydroxy nomifensine, 4'-hydroxy-3'-methoxy nomifensine and 3'-hydroxy-4'-methoxy nomifensine.

SummaryTo improve understanding of the relationships between gastric inhibitory polypeptide (GIP) and insulin secretion and food intake in obesity, immunoreactive insulin and immunoreactive GIP were measured in 5 obese children during PO glucose tolerance test carried out before and after diet.Before diet, mean insulin levels were normal at fasting and rose after glucose ingestion. The mean fasting immunoreactive GIP level was very high (1235 * U)9 pg/ml) compared to that of 8 healthy adult controls (411 f 44 pg/ml) and remained at this level throughout the test. There was only a short postabsorptive rise to 1515 * 158 pg/ml at 30 min, which was not significantly different either from the patients' basal values or from the 30-min control values (1356 f 67 pg/ml).After dieting for 3 to 7 months, immunoreactive insulia r e sponses returned to normal ranges. Concomitantly, both basal and total GIP release diminished significantly (basal GIP, 343 f 92 pg/ml, area under the GIP curve, 3820 and 1694 pg/ml/hr before and after diet, respectively). The postabsorptive GIP increment, however, rose significantly from 180 pg/ml,hr, before diet, to 665 pg/ml/hr afterwards. These results might be compatible with the hypothesis that in obesity, hyperinsulinemia, and overactivity of the GIP cells are associated phenomena caused by overeating and reversed by r e duced food intake. However, several contradictory fmdinps remain unexplained. The d i~c r e~a n &~ between insignificant postabsorptive GIP increments and elevated insulin resmnses before diet casts doubts on the causal relationship betwee;] GIP and insulin secretion. The small GIP rise might be due to a limited secretory capacity of the GIP cells or to a diminished stimulatory capacity of glucose. The constantly high level of GIP might reflect chronic hypersecretion and/or some defect in basal regulation and feedback control of GIP release.The change caused by dietary measures in the GIP secretion pattern provides evidence that in obese children, basal GIP secretion is influenced by nutritional factors. SpeculationIn spite of the small number of observations, the present Andings illustrate the complexity of the mechanisms governing the regulation of gastric inhibitory polypeptide and insulin release in obesity. It seems likely that basal gastric inhibitory polypeptide secretion is influenced by food intake, but further studies will be necessary to confirm that gastric inhibitory polypeptide plays a causal role in the hyperinsulinemia of obesity in children.

1. A radioimmunoassay (RIA) has been developed for determination of both nomifensine and total nomifensine (nomifensine + conjugated nomifensine) in serum, plasma, and urine. 2. Antibodies were prepared in rabbits by immunization with N‐(8‐Nomifensine) succinamic acid‐ bovine serum albumin. 3H‐labelled drug was used as tracer. Separation of free from antibody‐bound nomifensine was carried out using dextran‐ coated charcoal. For determination of total nomifensine, the acid‐ labile conjugate was split by acidification. 3. The limit of detection for nomifensine is 300 pg/ml plasma and the cross‐reactivity of the metabolites is less that 1%. The influence of conjugated nomifensine on the results of nomifensine can be corrected. 4. Pharmacokinetics of nomifensine were determined in healthy volunteers after oral administration of 100 mg 14C‐labelled drug. Peak levels of 14C radioactivity (2,150 ng/ml), total nomifensine (1,252 ng/ml) and nomifensine (53 ng/ml) appeared within 1.5‐2 h; the half‐life of elimination from plasma was 1.5‐2 hours. The advantages of this routine method are high sensitivity, the requirement of small amounts of plasma, and simple handling.

Experiments were performed in order to study a possible participation of gastrointestinal factors in the insulinotrophic action of glibenclamide in man. Six healthy volunteers received 5 mg glibenclamide in 50 ml saline orally. Biopsies were taken from the duodenal mucosa before and after administration of the drug. The duodenal insulin-releasing activity (DIRA) was assayed in the extracts of the biopsy material by using an in situ pancreas preparation of rat. The corresponding drug, IRI and glucose levels were measured in peripheral blood. The values of IRI correlated with both the prior elevation of DIRA and the increasing levels of the drug in the blood. These data indicate that glibenclamide might stimulate the release of gut factor(s) which, in turn, could possibly sensitize the pancrease response to the drug.