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The human bile duct has no intrinsic motility, but following cholecystectomy, flow through the bile duct is governed by the intraductal pressure generated by the liver, by the resistance to flow through the duct and sphincter at the terminal end of bile duct and by intraduodenal pressure. Pressure-flow experiments were performed upon 50 patients with biliary T-tube drainage following cholecystectomy and choledochostomy; nine patients had also undergone transduodenal sphincterotomy. Saline solution was introduced into the bile duct at controlled pressures, ranging from zero to 30 centimeters of water, while recordings were made of the flow rate of saline solution, intraduodenal pressure and respiratory movements. Although the flow rate of saline solution increased as its perfusion pressure was increased, three types of variation in flow were also recorded: rhythmic arrests of flow, occurring four to eight times per minute, believed to be due sphincteric contractions; nonrhythmic arrests of flow, lasting up to one minute, believed to be due to sphincteric contraction, and variations in flow associated with changes in intraduodenal pressure. The resistance to the flow of saline solution and the variations in flow rate were also similar in the patients who had undergone sphincterotomy. This study supports the view that sphincteric activity is present followingcholecystectomy, that the choledochal sphincter has rhythmic activity which differs from that of duodenal motility and that sphincter probably opens and closes continuously in a rhythmic manner during fasting periods in patients who have undergone cholecystectomy.

The effect of bile acid structure on biliary lipid composition was studied on the anesthetized bile fistula cat. The sodium salts of taurocholic acid, taurodeoxycholic acid, and taurochenodeoxycholic acid were infused intravenously in 6 animals in random order in a Latin square design. Bile acids were infused for 2 hr at approximately 270 mumoles per hr; each bile acid period was preceded by a 1-hr infusion of isotonic NaCl. Bile samples from the 2nd hr of bile acid infusion, a period of steady bile acid secretion, were compared, and their bile acid, cholesterol, and phospholipid contents were measured. Mean bile acid secretion rates did not differ among the three bile acids, nor did mean phospholipd secretion rates. In contrast, cholesterol secretion was 3 to 4 times greater with the dihydroxy bile acids than with the trihydroxy bile acid, taurocholic acid. It is concluded that bile acid structure is an important determinant of the lipid composition of bile. Further, this comparison of bile acids has dissociated cholesterol from phospholipid secretion, suggesting that bile acids may influence cholesterol and phospholipid secretion independently.

The transfer of cimetidine across the isolated perfused human placenta was examined. Placentas obtained at cesarean section were perfused for 2 hr from both maternal and fetal sides in constant flow recycling systems. Cimetidine was administered as a bolus dose to either the maternal circuit alone (n = 4) or to both maternal and fetal circuits simultaneously (n = 3), to achieve initial concentrations of 4 micrograms/ml. Antipyrine (20 micrograms/ml) and l-leucine (0.25 mM) were administered in like fashion as reference compounds. Two hours after maternal dosage there was equilibration of antipyrine across the placenta, but equilibration of cimetidine was incomplete (fetal/maternal ratio = 0.46 +/- 0.07). The fetal/maternal ratio of l-leucine was greater than unity; consistent with active maternal to fetal transport. Maternal to fetal cimetidine transplacental clearance (0.50 +/- 0.05 ml/min) was 23% of antipyrine clearance. After simultaneous dosage to both maternal and fetal circuits, the l-leucine fetal/maternal ratio was 1.37 +/- 0.08 at 2 hr and maternal and fetal levels of cimetidine and antipyrine were at equilibrium for the duration of the experiment (fetal/maternal ratio of cimetidine = 1.01 +/- 0.02). This study shows that cimetidine is transferred across the human placenta by passive diffusion. In contrast to the rapid placental transfer demonstrated by the majority of drugs studied previously, the placental transfer of cimetidine is slow. We conclude that the human placenta may therefore provide significant protection of the fetus from a single maternally administered dose of cimetidine.

The placental transfer and renal elimination of cimetidine were studied at steady state in near-term pregnant sheep. In seven nonanesthetized sheep, maternal dosage produced mean steady-state plasma concentrations of 776 +/- 217 ng/ml in the mother and 32 +/- 15 ng/ml in the fetus. Total cimetidine clearance was 41.63 +/- 9.10 liters/hr in the mother, whereas renal cimetidine clearance was 29.96 +/- 15.74 liters/hr in the mother and 1.53 +/- 0.48 liters/hr in the fetus. The mean ratio of cimetidine/creatinine renal clearance was similar in fetus and adult and was considerably greater than unity (7.5 and 7.1, respectively), suggesting active tubular secretion of equal efficiency in both. Fetal dosage in six of the nonanesthetized preparations reversed the maternal-fetal plasma cimetidine concentration gradient (fetal plasma = 16,895 +/- 5,507 ng/ml; maternal plasma = 513 +/- 184 ng/ml). At these very high fetal plasma concentrations, the mean fetal cimetidine/creatinine clearance ratio (2.1) was significantly lower, consistent with the saturation of an active renal tubular secretory process. In four anesthetized sheep, both maternal and fetal renal cimetidine clearances (9.83 +/- 5.39 and 0.32 +/- 0.14 liters/hr, respectively) were 70 to 80% lower than in nonanesthetized sheep. Umbilical venous and arterial cimetidine concentrations were similar (42 +/- 11 and 43 +/- 11 ng/ml, P greater than .05) but substantially less than the maternal plasma concentration (1535 +/- 500 ng/ml). Thus, the principal gradient occurs across the placenta rather than across the fetus. This suggests that, although the fetal kidney can extract cimetidine efficiently, low fetal drug concentrations are primarily due to the placenta and not to fetal drug elimination.

The effect of four bile acids, taurocholic (TC), taurochenodeoxycholic (TCDC), tauro-3 alpha,7 alpha-dihydroxy-12-keto-5 beta-cholanoic (T12K), and cholic (C), on bile lipid and water secretion was studied in the bile fistula cat over a 20-fold range of bile acid secretion rates. The critical micellar concentration (CMC) and lecithin-solubilizing capacity of TC, TCDC, and T12K were measured in vitro. T12K and C produced a greater choleresis than TC or TCDC; phospholipid secretion was strikingly reduced with T12K; and cholesterol secretion strikingly increased with TCDC, with a high cholesterol-phospholipid ratio. The estimated CMCs of TC, TCDC, and T12K were 3.3, 0.7, and 6.2 mM respectively; the relative lecithin-solubilizing capacities were 4.4:2.6:1. We conclude that the micellar characteristics of the bile acids studied do not explain the differences in water and lipid secretion observed, and that effects within the hepatocyte may be equally important.

Severe acute hypoxia is known to inhibit markedly the elimination of oxidatively metabolized drugs by the isolated liver. However, little is known of the degree of hypoxia required to produce inhibition of drug elimination by oxidative pathways in the intact organ. This study, in the isolated perfused rat liver, examined the oxygen dependence of the hepatic elimination of omeprazole, a drug which undergoes extensive oxidative metabolism in the rat. The relationship between hepatic oxygen supply and the production of omeprazole's oxidative sulfone and reductive sulfide metabolites was also examined. Rat livers were perfused at 15 ml/min with a perfusate containing 5 micrograms/ml of omeprazole in a single-pass design. Omeprazole clearance and the formation clearance of the two metabolites were measured in each liver during normal oxygenation, at different levels of hypoxia and after reoxygenation. There was a linear relationship between omeprazole clearance and oxygen delivery over the whole range studied. Production of the sulfone was similarly oxygen-dependent whereas the sulfide was only detectable after a significant reduction in oxygenation. In a further group of experiments the oxygen dependence of omeprazole clearance was shown to not be altered when the concentration of drug was lowered to 1 microgram/ml. This study shows that oxygen delivery is a critical determinant of the rate of oxidative drug metabolism in the isolated liver and supports the contention that reductions in hepatic oxygen supply may significantly alter the hepatic disposition of oxidatively metabolized drugs in vivo.

Summary: Giardiasis following gastric surgery. A patient is presented who developed acute life-threatening diarrhoea due to infestation with Giardia lamblia. We propose that the severity of the illness may have been related to hypochlorhydria following gastric surgery.

Repeated clinical and biochemical evaluations of liver function were performed on 60 patients taking sodium valproate. No clinical evidence of liver disease was found. Biochemical abnormalities were frequently found, but they were far more common in patients treated with multiple anticonvulsants than in patients on valproate alone. A control group of patients taking phenytoin or carbamazepine monotherapy also had a high incidence of biochemical abnormalities. A group of patients started on valproate therapy 6 years previously was followed up. No evidence of liver disease was found in this group. It was concluded that biochemical abnormalities of liver function in patients receiving valproate are not progressive, and in many cases relate to the intake of other drugs. The finding of abnormal liver function tests is not necessarily an indication for ceasing valproate.

Blood was withdrawn from the ante-cubital vein of five normal volunteers and the erythrocytes were washed and resuspended in isotonic saline. The rate of descent of the erythrocyte-saline boundary was measured every hour for a period of at least 4 h for different suspended cell concentrations. The velocity of this boundary remained constant during the period of observation for a specific concentration. There was, however, an experimental variation of sedimentation rate with red cell concentration. Extrapolation to zero concentration allowed the 'Svedberg constant' for normal red cells to be evaluated. A continuum physics theory was used to explain the observations. The sedimentation rate was also measured in anticoagulated whole blood. The rates of descent in whole blood and the red cell-saline suspension were significantly different. Furthermore, the erythrocyte boundary in whole blood displayed both acceleration and deceleration during the period of observation. These experiments support the concept, proposed in an earlier theoretical study, of an internal energy dissipative mechanism which occurs in heterogeneous fluids (such as blood) but not in homogeneous fluids (such as water).

SUMMARY 1. The effect of pretreatment with phenobarbitone on the hepatic transport of sodium 14C-taurocholate was studied in the Sprague Dawley rat. Taurocholate solutions were injected into the portal vein in a volume of 0.2 ml in 2 s. 2. Biliary secretion of taurocholate injected into the portal vein in a concentration of 25 μM was not altered by pretreatment with phenobarbitone. This concentration of taurocholate corresponds to that occurring normally in portal venous blood. 3. When taurocholate was injected in a much larger concentration (13 mM), biliary secretion of taurocholate was significantly slower in phenobarbitone-pretreated rats than in control rats. 4. Changes in hepatic bile salt transport do not appear to contribute to the choleresis that occurs with phenobarbitone.

The effect of five bile acids on biliary lipid secretion was studied in the pentobarbital-anesthetized cat. The dihydroxy acid, taurohyodeoxycholic acid, was indistinguishable from another dihydroxy acid, taurochenodeoxycholic acid, but secretion of both phospholipid and cholesterol was considerably reduced with two mono-keto dihydroxy acids, tauro-3alpha,12alpha-dihydroxy-7-keto-5beta-cholanoic acid and tauro-3alpha,7alpha-dihydroxy-12-keto-5beta-cholanoic acid. The effect of a trihydroxy bile acid, taurocholic acid was as previously described. The effect of the keto bile acids may be explained by the ability of these bile acids to solubilize lipid, but such an explanation is inadequate for the difference between di- and trihydroxy bile acids. An intracellular effect of bile acid is postulated.

The placental transfer, and maternal and fetal disposition, of the beta-adrenoreceptor blocking drug propranolol were studied in the pregnant sheep near term. In separate studies, propranolol (1 mg/kg) was administered peripherally or into the portal vein as an i.v. bolus, to either mother or fetus. Both mother and fetus were provided with vascular and bile duct cannulae, enabling plasma concentrations and biliary excretion of the drug to be measured over 6 hours. Placental transfer of propranolol was rapid and bidirectional. Comparison of the systemic blood levels obtained after peripheral and portal dosage indicated that hepatic extraction was much more efficient in the adult. This was supported by an apparent/true biliary clearance ratio of approximately 20 in the adult, and only 2-3 in the fetus. These studies show that the fetus near term is exposed to propranolol administered to the mother at a time when its ability to clear the drug is not fully developed.

Maternal and fetal disposition of the beta adrenoceptor blocking drug, propranolol was examined in the pregnant sheep from day 95 to day 140 (term, 145 days) of gestation. Propranolol was administered to the mother (bolus dose, 1.5 mg/kg followed by an infusion of 1.2 mg/kg/hr over 3 hr) to achieve an average steady-state maternal total drug concentration of 600 ng/ml. Total steady-state maternal plasma propranolol concentration was 666 +/- 266 ng/ml, reflecting a 4-fold variation in maternal drug clearance and a 14-fold variation in binding. Neither maternal clearance nor binding showed a significant change with gestational age. Total plasma drug concentrations in the fetus increased significantly with gestational age (r = 0.58, P less than .05), due to a concomitant increase in binding (r = 0.66, P less than .01). Fetal steady-state unbound drug concentrations were 50% of those seen in the mother, indicating that the fetus is capable of irreversible elimination of the drug. This ratio did not change with gestational age, suggesting that the capacity of the fetus to eliminate propranolol does not increase detectably in the latter part of pregnancy. The significant correlation between maternal and fetal unbound drug concentrations indicates that a major determinant of fetal exposure to propranolol is the clearance of the drug by the mother.

The plasma clearance and the liver uptake of intravenously administered (64)Cu were significantly impaired in four patients with Wilson's disease. These defects were unlikely to be simply expressions of the high liver copper concentration as the plasma clearance and hepatic uptake of (64)Cu were normal in four patients with primary biliary cirrhosis, in whom the liver copper concentration was raised to a degree comparable to that in Wilson's disease. The normal liver uptake and plasma clearance of (64)Cu in three patients with other forms of hepatocellular disease suggest that impaired liver cell function does not have a significant effect. The precise nature of the defect in copper transport in Wilson's disease remains to be elucidated; it is possible that delayed uptake of copper by the hepatic lysosomes may account for the toxic effects of the metal.

Cholate metabolism was studied in fetal dogs 1 wk before term and was compared with cholate metabolism in adult dogs. Tracer amounts of sodium cholate-(14)C were administered to the fetus in utero by intravenous infusion over 6 hr. Fetal plasma disappearance, biliary excretion, tissue distribution, and placental transfer of cholate were measured over 10 hr. Infused cholate-(14)C was cleared rapidly from fetal plasma principally by the fetal liver and to a minor extent by placental transfer to the mother. The taurine conjugate was formed in the fetal liver and was excreted into the proximal small intestine via the biliary tree. Indirect evidence for the functioning enterohepatic circulation of bile salt in the fetus was obtained. Comparison with the results of similar experiments in adult dogs showed that the fetal liver was almost as efficient as the adult liver in the uptake, conjugation, and excretion of tracer amounts of cholate-(14)C. The maximal rate of excretion of radiolabel attained by the fetus was somewhat slower than in the adult (82.8 +/-1.4% and 96.1 +/-4.0% [mean +/-SE] of the infusion rate, respectively), and the proportion of the total dose excreted by the fetal liver during 10 hr was smaller (81.4 +/-1.3% vs. 96.6 +/-4.4%). This difference could be only partly accounted for by placental transfer (2.8 +/-0.6% of the fetal dose). Labeled cholate and taurocholate were excreted by the fetus at similar rates, which suggests that, under the conditions of study, conjugation had little influence on the rate of transfer of cholate across the liver cell. It is concluded that the fetal dog, 1 wk before birth, has a remarkably mature and efficient mechanism for the uptake and excretion of cholate.

1. [14C]Cholesterol was administered intravenously via the umbilical vein to foetal sheep in the latter half of gestation, and the incorporation of radioactive label into foetal bile acids was assessed. 2. After 4 days, 0·5–2% of the radioactive label was found in foetal bile. Seventy to eighty per cent of the radioactive label in foetal bile was present as [14C]taurocholic acid and [14C]taurochenodeoxycholic acid. The remainder was [14C]cholesterol. No radioactive label was found in taurodeoxycholic acid, or in any of the glycine-conjugated bile acids. 3. It is concluded that the foetal sheep liver in the second half of gestation synthesizes taurocholic acid and taurochenodeoxycholic acid. However, the secondary bile acid taurodeoxycholic acid and the glycine-conjugated bile acids, present in foetal bile, have been acquired by placental transfer from the mother.

The optimal dose schedule for omeprazole in the treatment of peptic ulcers has not been established. Two recent comparative dose studies in small groups of patients showed rapid healing of duodenal ulcers treated with 20, 40 or 60 mg/day for 4 weeks (1, 2). We report a double-blind study comparing a lower dose of omeprazole than has previously been studied (10 mg/day) with an intermediate dose (30 mg/day).

Previous studies with omeprazole have demonstrated that a daily dose of 30 or 40 mg reduces the acidity of gastric contents throughout the 24-hour period (1, 2). The influence of dosing time has been examined with 40 mg given either in the morning or in the evening (1). A dose at 0900 hours produced a slightly greater overall elevation in 24-hour pH than did dosing at 2100 hours. Inhibition of gastric acidity was nearly complete with either regimen, so that the difference between them was of doubtful therapeutic significance. At a lower dose, which may be considered for maintenance therapy, the time of administration may be more important. Therefore, 24-hour gastric pH profiles were examined in duodenal ulcer patients given omeprazole, 10 mg, in the morning or the evening.