Pancreozymin bioassay in man based on pancreatic enzyme secretion: potency of specific amino acids and other digestive products.

The ability of products of digestion to stimulate pancreozymin secretion in man was investigated using a bioassay procedure, based on duodenal perfusion, which quantified the total outputs of pancreatic enzymes evoked by intraduodenal stimuli under steady-state conditions. Patterns of response resulting from physiologic intraduodenal concentrations of test material were basal output (with isotonic saline), washout of enzymes (with dextrose, micellar fatty acid, and amino acids), and sustained output of enzymes (with amino acids and micellar fatty acid). The sustained secretion of pancreatic enzymes found during the 2nd hr of perfusion and subsequently was characteristic of pancreozymin-induced secretion. The enzyme output in response to a mixture of essential and nonessential amino acids was significantly higher than that evoked by micellar fatty acid and was comparable with that resulting from the maximally tolerated dose of pancreozymin given by vein. Perfusion with essential amino acids caused enzyme outputs comparable to those induced by perfusion with the original amino acid mixture, whereas perfusion with nonessential amino acids had no effect. When the essential amino acids were tested individually, only phenylalanine, methionine, and valine caused significant increases in pancreatic enzyme output; the effect of tryptophan was indeterminate. However, the pancreatic enzyme output was less in response to these three essential amino acids than to mixtures containing all of them.

Regulation of pancreatic and gallbladder functions by intraluminal fatty acids and bile acids in man.

The effects of intraduodenal glycerol, fatty acid (FA) chain length and FA loads, and bile acid (BA) concentrations on pancreatic and gallbladder function were investigated in 31 healthy volunteers by a perfusion method. FA absorption rates in the duodenum and proximal jejunum were measured simultaneously. Pancreatic and gallbladder responses were augmented by increasing FA chain length and FA loads until the "maximal" secretory capacity of the pancreas and gallbladder emptying was attained. Glycerol had no effect. Raising BA concentrations above the critical micellar concentration accelerated FA absorption rates but decreased the magnitude of pancreatic and gallbladder responses to FA. Higher BA concentrations exerted an opposite effect, slowing FA absorption and increasing pancreatic and gallbladder responses. Indeed, a significant, inverse correlation was found between FA absorption and pancreatic and gallbladder responses to FA, suggesting a relationship between the length of intestine exposed to FA and the amount of cholecystokinin (and/or other neurohormonal factors) released, which stimulates pancreatic secretion and gallbladder contraction.

Interactions between intraluminal bile acids and digestive products on pancreatic and gallbladder function.

Interactions between bile acids (taurocholate, TC; taurochenodeoxycholate, TCDC; or taurodeoxycholate, TDC) and digestive products (essential amino acids, EAA or monoolein, MO) in the lumen of the proximal small bowel, affecting pancreatic enzyme secretion and gallbladder contraction, were studied in 77 healthy volunteers by a perfusion method. Perfusion of EAA or MO caused significant increases in pancreatic enzyme output together with gallbladder contraction; MO was more potent and induced enzyme outputs comparable to the maximal response attained with intravenous cholecystokinin-pancreozymin (CCK-PZ). Perfusion of TC alone had no effect, but addition of 10 mM of either TC, TCDC, or TDC to perfusates containing EAA, or 10 mM TC to MO, or both significantly reduced pancreatic enzyme output and prevented gallbladder contraction. A lower concentration of TC (5 mM) added to EAA also produced a significant inhibitory effect. Inhibition of the stimulatory action of digestive products occurred in the jejunum as well as in the duodenum. The inhibitory action of bile acid was considered to be intraluminal since (a) bile acid did not modify the effects of CCK-PZ given intravenously; and (b) the stimulatory effect of digestive products perfused in the duodenum on pancreatic and gallbladder function was not influenced by simultaneous perfusion of bile acid in the jejunum. It is proposed that this inhibitory effect of bile acid is mediated through inhibition of CCK-PZ secretion by high intraluminal concentrations of bile acid. Inhibition of CCK-PZ secretion by bile acid may contribute to the regulation of pancreatic and gallbladder function during digestion by reducing pancreatic enzyme secretion and permitting the gallbladder to refill after evacuation of its contents.

Comparative serum prednisone and prednisolone concentrations following administration to patients with chronic active liver disease.

Following administration of equivalent oral doses (30mg) of either prednisone or prednisolone to 5 patients with chronic active liver disease who had failed to respond to therapy, 5 patients with chronic active liver disease in remission induced by prednisone, and 7 healthy volunteers, corticosteroid concentrations were measured in both serum and urine by radioimmunoassay. Prednisone and prednisolone concentrations in the urine were very similar in all groups, regardless of the drug given. After either treatment, the peak serum concentration and area under the prednisolone serum concentration-time curve were 4 to 5 times those of prednisone. Slight differences among the 3 groups studied were seen in prednisone and prednisolone pharmacokinetics, but none was significant. It is concluded that the use of prednisone instead of prednisolone to treat chronic active liver disease can not be implicated as a cause of treatment failure. Indeed, this study suggests that either medication is effective, and this is supported by serum concentrations which suggest a rapid interconversion equilibrium between the 2 corticosteroids.

Alpha1-antitrypsin phenotypes in chronic active liver disease and primary biliary cirrhosis.

Alpha1-antitrypsin concentrations and phenotypes were determined in groups of patients with chronic active liver disease and primary biliary cirrhosis. The concentrations of alpha1-antitrypsin were above normal values in both groups; the patients with primary biliary cirrhosis had higher concentrations than those with chronic active liver disease. The prevalence of common phenotypes in these two groups did not differ from that in a sample of healthy blood donors from this institution of from a large Norwegian sample. We interpret our data as disputing the view that alpha1-antitrypsin phenotypes, other than Z. significantly predispose adults to hepatic cirrhosis.

Development of radioimmunoassays for prednisone and prednisolone. Application to studies of hepatic metabolism of prednisone.

Radioimmunoassays for measuring prednisone and prednisolone (delta1 corticosteroids) in serum have been developed. By using 6,7-3H-delta1 corticosteroids as tracer, rabbit antibodies against delta1 corticosteroid-21-hemisuccinate in bovine serum albumin, and ammonium sulfate precipitation, the assays detected less than 0.8 ng/ml of delta1 corticosteroid and interassay coefficients of variation were less than 8.5 %. The specificity of antibodies, tested against all drug metabolites and major endogenous steroids, showed that only 21-glucuronic acid esters of delta1 corticosteroids had cross-reactivity of possible clinical importance. Assays were validated by measuring levels in samples of fastingstate sera with or without adding known amounts of prednisolone. Measurements of serum concentrations of both prednisone and prednisolone in normal dogs and in those with hepatic vascular exclusion were made after intravenous administration of prednisone. Although high levels of prednisolone appeared rapidly in normal dogs, only slight amounts were measured in dogs with hepatic vascular exclusion, which emphasized the importance of the liver in the conversion of prednisone to prednisolone, its active metabolite.