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B Bona

Publications and source records attributed to B Bona.

6 recordsLinked to original sources
PubMed1987

Simulation of the metabolism and enterohepatic circulation of endogenous deoxycholic acid in humans using a physiologic pharmacokinetic model for bile acid metabolism.

The metabolism and enterohepatic circulation of deoxycholic acid (DCA), a major secondary bile acid in humans, was simulated using a linear multicompartmental physiologic pharmacokinetic model. The model was similar to that previously reported and used to simulate the metabolism of cholic acid and chenodeoxycholic acid, but differed in two respects: (a) the input of newly formed DCA molecules originated from colonic absorption rather than from de novo hepatic biosynthesis and (b) a new type of transfer coefficient was proposed to describe the movement of DCA molecules from an insoluble, bound compartment to a soluble compartment. Simulations were performed to define the effect of varying fractional colonic absorption (from 0.1 to 0.6) as well as varying fractional formation of DCA from cholic acid (from 0.3 to 1). The simulations indicated that the exchangeable total DCA pool expanded up to 12-fold as fractional colonic absorption was increased from 0.1 to 0.6. The fractional turnover rate of the DCA pool showed a corresponding decrease. Increased conversion of cholic acid to DCA had an effect on DCA pool size that was similar to that resulting from increased colonic fractional absorption. So long as ileal absorption was efficient, the "soluble" colonic pool of DCA remained small relative to other organ pools, and the absorption of unconjugated DCA from the colon was less than 10% of the total DCA absorption from the ileum. It is proposed that the relatively large proportion of DCA in the biliary bile acids of white adults in the Western world as compared with that of most other mammals is attributable to (a) a high fractional absorption of DCA because of a diet relatively low in fiber, (b) the absence of hepatic 7-hydroxylation of DCA, and (c) effective competition by DCA conjugates for active transport by the terminal ileum.

Biliary Tract↗
PubMed1986

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model.

The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine 'spaces' based on anatomical and physiological considerations (liver, gall-bladder, bile ducts, duodeno-jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall-bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time-dependent by incorporating meals which trigger gall-bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno-jejunum and the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24-h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.

Bile Acids and Salts↗
PubMed1986

Sorbitol clearance: a parameter reflecting liver plasma flow in the rat.

According to the clearance concepts, the functional liver plasma flow may be directly measured from the plasma kinetics of any substance whose hepatic intrinsic clearance largely exceeds liver perfusion. The present study was designed to ascertain the requirements for the reliability of D-sorbitol plasma clearance in evaluating changes of liver perfusion in the male Wistar rat. The plasma disappearance curve of D-sorbitol (3 mg/100 g b.w. by bolus i.v. injection) followed a first order kinetics and fitted a two-compartment model. Very similar estimates of D-sorbitol plasma clearance were obtained by applying the area under the curve method to data obtained by the trapezoidal rule and by compartmental analysis. D-sorbitol hepatic extraction was almost complete in controls and in rats submitted to porta-caval shunt and hepatic artery ligation, while significantly decreased after partial hepatectomy. Renal output never exceeded 10% of the administered amount. No in-vivo diffusion into red cells was observed. In controls, the functional liver plasma flow, as measured by D-sorbitol clearance was 2.83 +/- 0.68 ml/min/100 g (mean +/- SD). Significantly lower values were found in rats submitted to porta-caval shunt (1.19 +/- 0.38), hepatic artery ligation (2.06 +/- 0.53), and partial hepatectomy (1.03 +/- 0.44).

Animals↗
PubMedDate not supplied

Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model.

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.

Bile Acids and Salts↗
PubMedDate not supplied

SEQUAL: an interactive computer program for sequential classification of biomedical data.

A computer program for sequential bayesian classification of patterns defined by integer and real-valued data is described. Classified patterns from a training sample are used to estimate the non-parametric (kernel) probability density functions and the a-priori class probabilities necessary to implement the bayesian classification. For each pattern and at each step in the sequential program, the 'best' feature to be measured at the next step is computed on the basis of the estimated misallocation error rate. The user can actually use the proposed feature or any other one; once the chosen feature has been measured, its value is used to allocate the pattern into the class with the highest conditional a-posteriori probability, according to the Bayes formula. The main feature of the program consists in the computation of the 'probability of reversal' at each step of the sequential procedure. The probability of reversal represents the probability that at the next step the pattern will be classified into a class different from the present one. The probability of reversal can be used as a stopping criterion, which is more efficient than other commonly used stopping rules, such as the a-posteriori Bayes probability or the estimated misallocation error rate. The program, available in FORTRAN 77 for a VAX/VMS machine, has been tested both on simulated and real data collected from patients suffering from various forms of hepatic disease.

Bayes Theorem↗