[Biliary excretion of choleretically active cinnamic acid derivatives in the rat]. / Die biliäre Ausscheidung choleretisch aktiver Zimtsäure-Derivate durch die Ratte.

Concerning the well-known choleretic effect of ferulic acid, we made further investigations on biliary excretion, metabolism and bile flow after application of ferulic acid and related compounds. In anesthesized bile duct cannulated male Wistar-rats, we studied the biliary excretion of the following 14-C labelled cinnamic acid compounds: caffeic acid (CA), ferulic acid (FA), m-coumaric acid (mCA), p-coumaric acid (pCA), isoferulic acid (IFA), p-methoxycinnamic acid (pMCA), 3,4-dimethoxycinnamic acid (DMCA), and 3,4,5-trimethoxycinnamic acid (TMCA). These compounds were given intraduodenally (128-384 mumoles/kg b. wt.). All of the tested compounds were excreted to some extent in bile, giving a bile to the serum conc. ratio greater than 1. The radioactivity excreted by bile within 2 hours (as percent of the given dose) was about 20% in the case of FA, IFA, DMCA, and TMCA, about 8% for pMCA, and less than 5% for CA, mCA and pCA. The biliary excretion increased in a dose-dependent manner only after FA and IFA, but not after application of the other compounds.

[Reciprocal action between caffeine, other stimulants and drugs]. / Wechselwirkungen zwischen Coffein, anderen Genussmitteln und Arzneistoffen.

Caffeine is ingested not only with beverages as coffee, tea, coca-cola but also in form of many analgetic drugs. Therefore interactions of this substance with other biologically active substances and drugs should be expected, and the knowledge of these would be of practical importance. The interactions between caffeine and alcohol, smoking, salicylic acid, phenacetin, barbiturates, and theobromine are described.

[Modification of the caffeine metabolism in mouse liver slices by previous treatment of the experimental animals with ethanol, aminophenazone and phenobarbital]. / Metabolisierung von Coffein durch Leberschnitte der Maus und deren Beeinflussung durch Athanol und Aminophenazon sowie Phenobarbitalvorbehandlung der Versuchstiere.

The influence of ethanol, aminophenazon, and phenobarbital on the caffeine metabolism of mice liver slices was tested using 1-methyl-14C-caffeine as the marker substance. In these experiments the following results were obtained: 1. Caffeine metabolism was increased by the extension of the incubation time. The caffeine metabolism increased almost linearly up to 60 min, and during this time 109.5 nmol caffeine were metabolized per gram liver wet weight. 2. Ethanol decreased the caffeine metabolism of mice liver slices. Ethanol concentrations of 23.36, 46.72 and 93.44 mM showed a clear and dose-dependent inhibition of caffeine metabolism, reaching a maximal value of 67.1%. 3. Aminophenazon also decreased the metabolism of caffeine. This effect was augmented by increasing the concentrations of aminophenazon (10.4, 20.8, 41.6, 104.0 M) and an inhibition of 63.8% was observed after giving the highest concentration. 4. Pretreatment of mice with phenobarbital, producing an enzyme induction of the liver, clearly increased the metabolism of caffeine of mice liver slices. Under these conditions, the caffeine metabolism was increased by more than 300%. 5. In contrast to liver slices no important caffeine metabolism could be detected in kidney or brain slices of mice. 6. Mice liver slices were able to metabolize caffeine more quickly than liver slices of the rat. Within 60 min the metabolized caffeine per gram liver wet weight was more than twice higher for mice as compared to rats.

[Pharmacokinetics of caffeine in mice and its modification by ethanol]. / Untersuchungen an Mäusen zur Pharmakokinetik von Coffein und deren Beeinflussung durch Athanol.

In experiments on mice the pharmacokinetics (absorption, distribution, metabolism) of orally administered caffeine (18 mg/kg) using 14C caffeine as marker and the influence of simultaneously applied ethanol (1,8 g/kg) was tested. The following results were obtained: 1. Caffeine was very quickly absorbed from the gastro-intestinal tract of mice. Addition of ethanol had no noticeable influence on the absorption of caffeine. 2. The elimination of caffeine from the serum and tissues examined (liver, kidney, brain, muscle) showed an exponential course with a half life of 40-60 minutes and was completed after 4 to 5 hours. 3. By giving ethanol the elimination of caffeine was significantly decreased and its half life increased to 160-240 minutes. 4. The caffeine metabolites reached their maximal concentration in serum and tissues examined within two hours. In the liver and kidney the concentration of caffeine metabolites was greater than in the serum, whereas they were lower in the brain and muscle. At the end of the experimental the concentration of caffeine metabolites reached only very low values. 5. After administration of ethanol the caffeine metabolites were significantly decreased from the 30th to 180th minute in the liver and kidney; they were only slightly lowered in the serum and almost unchanged in the muscle and brain. The results of these experiments suggest that ethanol inhibits the metabolism of caffeine in the liver, especially by influencing its demethylation to other dimethyl- and monomethylxanthines and probably also its oxidation ot methyluric acids.

Effect of portacaval shunt on biliary cholesterol and bile salt secretion in normal rats.

In order to assess the role of bile secretion in the serum cholestrol lowering effect of a portacaval anastomosis in rats, bile flow rate, bile salt and cholesterol secretion in bile were determined. The study comprised five groups of animals: (1) rats with protacaval shunt cholesterol free food ad libitum. (2) sham-operated and pair-fed controls; (3) unoperated, pair-fed controls; (4) unoperated controls on cholesterol free diet ad libitum; and (5) unoperated controls on normal laboratory rat chow ad libitum. Bile flow rate showed no difference in any of the groups on cholesterol free diet. Bile salt secretion was significantly elevated in shunted animals (87.1 +/- 7.0 nmol/min) as compared with pair-fed sham-operated (64.7 +/- 20.0 nmol/min) and unoperated controls (56.0 +/- 22.3 nmol/min). Biliary cholesterol output tended to be higher in shunted animals but this was not statistically significant. The data indicate that the atrophied rat liver in shunted animals is able to maintain a normal bile flow and to increase bile salt secretion. Thus, the serum cholesterol lowering action of a portocaval anastomosis may be partly due to an increased cholesterol catabolism to bile salts.

[Drugs and vitamins]. / Arzneimittel und Vitaminversorgung.

Since most of the drugs are taken orally via the gastrointestinal tract, interactions with food ingredients may lead to alterations in the intake of essential dietary factors. With regard to vitamins the following effects have been demonstrated: early decomposition resp. inactivation, decreased absorption or a qualitatively and quantitatively modified metabolism. Examples of such changes are given with regard to water- and lipid-soluble vitamins.

[Studies on the pharmacokinetics of C-14 cinnamic-acid derivatives in rats]. / Untersuchungen der Pharmakokinetik von 14C-Zimtsäure-Derivaten an Ratten.

Using some 14C-labelled derivatives of cinnamic acid which are of interest as metabolites of chlorogenic acid we studied their pharmacokinetic behaviour in rats. The absorption rate constant from intestinal was 2--10 times greater than the elimination rate constant. After i.v. application the half life of elimination from the blood was between 13 and 37 minutes. When greater amounts (50 mg/kg) were given by i.d. application, absorption and elimation were delayed. The tested compounds were excreted mainly by the kidneys and most of the given dosis could be found in urine within 2 hours. The biliary excretion differed widely among the tested compounds: only up to 3% were excreted in the bile in the case of m-cumaric acid, p-cumaric acid and caffeic acid, whereas up to 30% were found when ferulic acid or trimethoxycinnamic acid were given. From these results a greater ole of caffeic acid in the enterohepatic circulation is not to be expected.

[Coffee and health]. / Kaffee und Gesundheit.

Coffee as a rule develops stimulating effects on the central nervous system, heart and circulation which are mainly caused by caffeine. In certain cases coffee may also have a sedative effect and sometimes even it is useful to fall asleep quickly. Furthermore coffee may be advantageous in the treatment of some functional disorders caused by lacking of dopamine, because coffee is able to increase the dopamine formation in brain. Concerning the effects of coffee in the gastrointestinal-tract and liver-bile system caffeine is only of secondary importance. Hereby certain roasting substances, possibly also chlorogenic acid or caffeic acid should be responsible for the stimulating effects observed in these organs. These stimulating effects could be caused whether directly or indirect e.g. by liberating gastrin or other gastrointestinal hormones. Vitamin niacin, which is formed in greater amounts from trigonelline during the roasting process, may also be important from the nutritional standpoint. Therefore coffee may be prescribed as a true drug in cases of deficiency in vitamin niacin or also in the pellagra disease. By extensive epidemiological studies performed lately it could be demonstrated that there exists no correlation between coffee consumption and certain risk factors as hypertension, heart infarction, diabetes, gout or cancer diseases. Furthermore there was no evidence that coffee or its caffeine content are able to induce genetic alterations or even malformations.

Excretion of sulfobromophthalein in rats with iodomethane-induced depletion of hepatic glutathione.

Male urethane-anesthetized Wistar rats with biliary fistulas were infused for 60 min i.v. with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) at 594 nmol/100 g/min. Thirty minutes prior to the start of the infusion, 20 mg/kg iodomethane, dissolved in oliver oil, was given into the duodenum. The control received oil only. At the start of the infusion the hepatic concentration of GSH was 0.96 +/- 0.23 mg/g liver in the iodomethane-treated animals versus 1.93 +/- 0.13 mg/g liver in the control (P less than 0.001). When unconjugated BSP was infused, the excretion of total BSP (unconjugated plus conjugated) was markedly lower in the iodomethane-treated group than in the control. This difference was due solely to differences in biliary appearing conjugated BSP; the excretion of unconjugated BSP was identical in both groups. The different excretion patterns were paralleled by equal hepatic accumulation of total BSP in both groups. The ratio of unconjugated BSP/BSP-GSH in the liver was about twice as high after pretreatment with iodomethane than in the control group. When BSP-GSH instead of BSP was infused, the excretion rates of this dye were identical in both groups. The maximal transport capacity (Tm) was double that observed with infusion of unconjugated BSP in control animals. There is indirect evidence that BSP and BSP-GSH might have different excretion pathways.

Influence of dehydrocholate sodium on the biliary reabsorption of sulfobromophtalein sodium from the rat biliary tree after retrograde intrabilary injection.

Bilary re-excretion of sulfobromophthalein sodium (BSP) (1.2 mumol/rat) after retrograde intrabilary injection is markedly inhibited by dehydrocholate sodium (Decholin) given intravenously as a constant infusion (3.1 mumol/min/kg body weight) or as a bolus injection (24.8 mumol/rat) to rats. Most interestingly Decholin demonstrates the same inhibitory effects on the biliary re-excretion of BSP when it is administered by retrograde intrabiliary injection (24.8 mumol/rat) together with the dye. In contrast to the inhibition of biliary re-excretion of BSP its biliary reabsorption from the biliary tract seems to be rather increased: about 80-85% of 1.2 mumol BSP are reabsorbed in all sets of experiments with Decholin in comparison to about 65% to the control group. Combined with histological data it is suggested that reabosorption of BSP after retrograde intrabiliary injection occurs at the ductular site whereas re-excretion takes place at the cannalicular membrane of the hepatocyte.

[Interactions between nutrition and drugs]. / Wechselwirkung zwischen Ernährung und Arzneimitteln

It is only recently that the question of interaction between nutrition and drugs has been investigated. Generally there are two ways by which such an interaction may occur. On the one hand the food-intake and its composition may influence the effects of drugs by altering their pharmacokinetics. In most cases the abosrption of drugs and thereby also their biological effects are decreased when they are taken together with food, by only a few drugs the opposite effects have been observed. Furthermore the biotransformation of drugs may be inhibited by giving a diet poor in proteins. A diet rich in meat or in vegetables may also influence the urine pH in the more acid or basic direction and in this way the renal excretion of drugs may be changed considerably since drugs are generally either weak organic acid or bases. On the other hand drugs may also interfere with the availability and utilization of certain nutrients e.g. vitamins, electrolytes or trace elements. Such interaction could be observed when giving for example antibiotics, alcohol, contraceptives, anticonvulsives or laxatives over a long period. Deficiency of certain nutritional factors or even diseases can then be the consequence of such interactions.

[Metabolic effect of coffee and caffeine]. / Stoffwechselbeeinflussung durch Kaffee und Coffein

Coffee and its most important constituent, caffeine, may not only stimulate the function of many organs but also increase the metabolism in the body. These effects require a higher energy production which is mainly obtained from striated muscles by glycogenolysis and from fat tissue by lipolysis. Sutherland and Butcher were able to demonstrate that these degradation processes are primarily caused by an increase of cyclic 3,5-AMP. - In this connection caffeine and other methylxanthines are of special interest because these compounds also increase the intracellular amount of cyclic 3,5-AMP. This effect may be caused by an inhibition of phosphodiesterase, a release of catecholamines with resulting stimulation of adenylcyclase or by competitive inhibition of adenosine. At the present time it cannot be said which of these mechanisms primarily is involved in the in vivo effects of caffeine and other methylxanthines.

[Teratogenic and mutagenic studies with caffeine in the animal experiment]. / Teratogenetische und mutagenetische Untersuchungen mit Coffein im Tierexperiment

Principles of teratogenic and mutagenic actions are defined. The recent experimental studies with laboratory animals, and our investigations with caffeine-sodium benzoicum and with soluble coffee in pregnant rats and mice showed no teratogenicity. The results are compared with specific teratogenic effects of cytostatic agents. A teratogenicity of caffeine can be excluded, a mutagenicity in animal experiments can also not be proved.

The influence of cholic acid and dehydrocholic acid on the biliary excretion of unconjugated and conjugated sulfobromophthalein in rats.

Urethane anesthetized Wistar rats with biliary fistulas were infused during 100 min with sulfobromophthalein (BSP), the glutathione conjugate of sulfobromophthalein (BSP-GSH), cholic acid (CA) and dehydrocholic acid (DCA). The dyes (594 nmol/100 g/min) and the bile acids (1200 nmol/100 g/min) were infused separately, and in combination as well. When BSP was infused, CA and DCA increased the maximal excretion of total BSP (conjugated plus unconjugated) from 1400 to 4100 and 3300 nmol/100 g/10 min. The bile flow observed with BSP plus CA was not significantly different from that with BSP plus DCA. The biliary excretion of total BSP was higher throughout with CA than with DCA because CA increased the biliary concentration of PSP while DCA did not. The bile flow attained with CA alone was significantly lower than that with BSP plus CA. The current data provide arguments for abandoning the view that choleresis per se is the crucial determinant for BSP excretion. When BSP-GSH was infused instead of BSP, the excretion rate of the dye was not altered by the additional infusion of CA whereas it was significantly reduced by DCA. The maximal biliary concentration of BSP-GSH fell from 25.9 nmol/mul to 15.3 and 9.4 nmol/mul with CA and DCA, respectively. Both CA and DCA impaired the hepatic uptake of BSP and BSP-GSH. During the infusion with CA, BSP plus CA and BSP-GSH plus CA the biliary excretion rates of bile acids did not differ significantly from each other. This favours the view that the transfer for CA from the liver to bile is different from that for BSP and BSP-GSH. A fraction of bile fluid "independent of choleretics" (viz. of bile salts, BSP and BSP-GSH) is estimated and discussed in view of the different types of infusion.

Differences of reabsorption of unconjugated BSP and BSP-glutathione from the rat biliary tree after retrograde intrabiliary injection.

It has been shown that water and electrolytes are reabsorbed from the biliary tract of the rat. Furthermore there are some suggestions for the reabsorption of organic compounds during their passage down the biliary tract. Our results presented in this paper demonstrate a different mode of biliary excretion of unconjugated BSP [BSP-U] and BSP- glutathione [BSP-GSH] after retrograde intrabiliary injection, BSP-GSH is excreted to a much greater extent than BSP-U within the first 5 minutes after retrograde administration. In other terms BSP-GSH is reabsorbed to a lesser extent than BSP-U. Additionally the reabsorption of BSP-U and BSP-G after retrograde injection seems to be dependent on the concentration and the contact time in the biliary tree. It is suggested that the different biliary excretion of BSP-U and BSP-GSH after intravenous injection might be explained partly by a different reabsorption mode.