Intestinal solubilization, absorption, pharmacokinetics and bioavailability of chenodeoxycholic acid*

Abstract. Little is known about the physical state, intestinal solubilization, absorption and bioavailability of chenodeoxycholic acid used in the medical treatment of gallstones. Therefore the concentrations of unconjugated chenodeoxycholic acid were measured in the supernatant and precipitate phases of intestinal contents aspirated from stomach, duodenum and jejunum of nine control subjects who took 500 mg chenodeoxycholic acid (4 times 125 mg gelatin-coated capsules) either fasting or together with a standard liquid meal. Chenodeoxycholic acid solubility was markedly influenced by luminal pH but was little affected by endogenous conjugated bile acids when their concentrations were > 1–2 mmol/1.
Systemic bioavailability of 250, 500 and 750 doses of chenodeoxycholic acid was measured in five subjects by comparing areas under 4 h serum concentration-time curves after giving the bile acid first as a bolus intraduodenal aqueous infusion of ³H-labelled chenodeoxycholic acid containing either ¹⁴C-polyethylene glycol or bromsulphthalein as non-absorbable markers, and then as gelatin-coated capsules by mouth.
Absorption was assessed by measuring the ratio of marker: bile acid in intestinal contents aspirated for 2 h from sites 60 and 120 cm distal to the duodenal infusion port and in three subjects quantitative recovery of marker was measured proximal to an occluding intestinal balloon. Absorption of duodenally-infused chenodeoxycholic acid was 96–99% complete and bioavailability was complete with the 250 and 500 mg doses but fell to 81% with the 750 mg dose.     

Intestinal absorption and biliary secretion of ursodeoxycholic acid and its taurine conjugate

BACKGROUND: Ursodeoxycholic acid (UDCA) and its taurine conjugate (TUDCA) exert a protective effect in cholestatic liver diseases. A greater hepatoprotective effect of TUDCA has been suggested. Absorption appears to be a limiting factor and up to now has not been studied in man. METHODS: We studied absorption and biliary bile acid secretion and composition after administration of UDCA and TUDCA in patients who had complete extrahepatic biliary obstruction caused by pancreatic carcinoma but had no intestinal or liver disease. After 5 days of intact enterohepatic circulation eight patients with a percutaneous biliary-duodenal drainage received, during two study periods, 1000 mg (1916.9 micromol; mean 29.6 micromol kg(-1)) TUDCA and 750 mg (1910.4 micromol; mean 29.5 micromol kg(-1)) UDCA in random order. Each patient served as his own control. RESULTS: After UDCA and TUDCA administration the biliary UDCA content increased to 55.2% and 54.6% of total bile acids, respectively (not significant). Biliary secretion of cholic and chenodeoxycholic acids remained unchanged whereas that of lithocholic acid increased slightly. A total of 64.6% of the orally administered TUDCA and 55.1% of the UDCA was absorbed (not significant). After TUDCA administration, biliary UDCA was preferentially (95.4%) taurine-conjugated whereas after UDCA administration biliary UDCA was mainly (79.8%) glycine-conjugated. CONCLUSIONS: After oral administration of TUDCA and UDCA, no significant differences in their absorption and in biliary bile acid secretion exist. Whether biliary enrichment with taurine conjugates of UDCA instead of glycine conjugates offers advantages in the treatment of cholestatic liver disease is unclear at present.     

Vanadium pharmacokinetics and oral bioavailability upon single-dose administration of vanadyl sulfate to rats

Vanadium pharmacokinetic parameters and oral bioavailability were determined after administration of vanadyl sulfate, an antidiabetic agent, to male Wistar rats. An optimal sampling design was used over a 21-day period; vanadium was measured in blood by atomic absorption spectrophotometry (AAS). After i.v. bolus injection (3.025 mg V/kg body weight), a three-compartment model was fitted to the data. Mean (+/- SD) half-lives were 0.90 +/- 0.56 hours, 24.8 +/- 14.5 h and 201 +/- 74 h, respectively, for the three phases observed. Vanadium clearance averaged 37.6 +/- 15.8 mL/h. Initial volume of distribution was 2.43 +/- 1.22 L/kg whereas total volume of distribution was 25.4 +/- 3.9 L/kg; these values largely exceeded body weight (i.e. 300 g), in agreement with a great uptake and retention of vanadium in tissues. After oral gavage administration (15.12 and 7.56 mg V/kg body weight), vanadium disposition was best described by a three-compartment model, with absorption appearing to occur by a zero-order rate. This process lasted 10.3 +/- 1.3 h and 10.9 +/- 1.1 h for the two dosage levels, respectively. Half-lives corresponding to the terminal log-linear part of the curve were 173.5 +/- 1.6 h and 172 +/- 6 h (Bayesian estimates). No dose-dependency was observed for any of the parameters determined. Absolute bioavailabilities, with reference to the i.v. administration, were 12.5% and 16.8% when determined from AUCmod. Bioavailability appeared to be higher than generally stated in the literature.     

Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man

The bioavailability of ursodeoxycholic acid (UDCA), a cholesterolic gallstone dissolving agent, has been analysed in seven healthy human volunteers. After absorption of a capsule containing a 500 mg dose, the time course of plasma concentrations of the drug presented a double peak profile over a 240 min period. In order to explain this result, a second group of five subjects bearing a four-way jejunal catheter fitted with an occluding balloon, received an oral dose of 250, 500 or 750 mg of the drug. Simultaneous analyses of plasma UDCA concentrations and jejunal UDCA contents were carried out. UDCA is poorly soluble in the gastro-duodeno-jejunal contents of fasted subjects since 21-50% of the ingested doses were recovered in solid form. The profile of plasma concentration paralleled the amount of soluble UDCA present in intestinal lumen. When jejunal contents were infused below the balloon a second plasma peak appeared in cases corresponding to ingestion of higher doses of UDCA. In conclusion, pharmacological doses of UDCA are not readily soluble in the stomach and intestine of a healthy fasting man. In consequence, the bioavailability of the drug varies with its progressive solubilization in the gastrointestinal tract. The present results suggest that repeated daily doses of UDCA should improve its bioavailability in treated gallstone patients.     

Effects of administration route on valproate pharmacokinetics in the rabbit

The absorption of sodium valproate was studied in 5 rabbits. Each animal received the drug (70 mg/kg) via 3 routes: intravenous, gastric and duodenal. For the 2 extravascular routes, the absolute bioavailability F, maximal plasma concentrations Cmax, times to peak Tmax and absorption coefficients Kabs were the same. Absolute bioavailability was always close to unity. This indicated that valproic acid was absorbed from the intestine as well as from the whole gastrointestinal tract. The other pharmacokinetic parameters such as terminal plasma half-life, total clearance and volume of distribution remained unchanged whatever the route of administration.     

Arachidonic acid absorption in human jejunum in organ culture: effects of ethanol

Human jejunal tissue obtained by peroral biopsy was cultured in control medium and in medium containing 100 mmol l-1 ethanol. Subsequently, the incorporation and metabolism of [3H]-arachidonic and [14C]-linoleic acid were evaluated. Of the two fatty acids a significantly higher amount of [3H]-arachidonic acid was incorporated into phospholipids and more [14C]-linoleic acid was incorporated into triacylglycerols. This preferential distribution of the labelled fatty acids was not affected by ethanol, but when ethanol was present in the tissue culture medium, there was a significant decrease in the incorporation of both fatty acids into tissue phospholipids. The study thus shows that ethanol in moderate concentrations can affect human jejunal absorption and metabolism of polyenoic fatty acids, contributing to a decrease in the amount of eicosanoid precursors available in jejunal tissue.     

Motility- and blood flow-dependent absorption of amino acids in canine small intestine.

A relationship between L-phenylalanine and L-serine absorption, intestinal motility and blood flow has been studied with a canine in situ isolated jejunal loop in acute experiments and in chronic preparations in conscious dogs. During spontaneous rhythmic contractions, as well as after mechanical and pharmacological stimuli, rhythmic changes in blood flow, related to intestinal contractions, were observed. They had no bearing on mean blood flow or absorption as long as they did not occur together with tonic contractions. The tonic contractions resulted in a prolonged decrease in jejunal blood flow ano diminished amino acid absorption rate. Absorption and motility index, as well as blood flow and motility were negatively correlated. There was a positive rectlinear correlation between intestinal blood flow and absorption, regardless of whether changes in blood flow resulted from the increase in motility or were induced by intestinal artery occlusion. These correlations suggest that changes in amino acid absorption during increased motility depend on changes in blood flow. This relationship may be important in clinical syndromes with hypermotility.     

A first‐in‐human study of the safety,tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086, an anti‐tissue factor pathway inhibitor mAb,in healthy volunteers

Essentials

• Tissue factor pathway inhibitor (TFPI) is an antagonist of FXa and the TF‐FVIIa complex.
• PF‐06741086 is an IgG₁ monoclonal antibody that targets the Kunitz‐2 domain of TFPI.
• Single doses of PF‐06741086 were evaluated in a phase 1 study in healthy volunteers.
• Data from this study support further investigation of PF‐06741086 in individuals with hemophilia.

Summary

Background

Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of the tissue factor–activated factor VII complex and activated FX. PF‐06741086 is a mAb that targets TFPI to increase clotting activity.

Objectives

This study was a randomized, double‐blind, sponsor‐open, placebo‐controlled, single intravenous or subcutaneous dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086.

Patients/Methods

Volunteers who provided written informed consent were assigned to cohorts with escalating dose levels. Safety endpoints included treatment‐emergent adverse events (TEAEs), infusion/injection site reactions, vital signs, electrocardiogram, and coagulation and hematology laboratory parameters. Pharmacokinetic (PK) and pharmacodynamic (PD) endpoints included exposures of PF‐06741086 in plasma and measures of PF‐06741086 pharmacology, respectively.

Results

Forty‐one male volunteers were recruited overall. Thirty‐two were dosed with PF‐06741086 from 30 mg subcutaneously to 440 mg intravenously. All doses were safe and well tolerated. TEAEs were mild or moderate in severity, laboratory abnormalities were transient, there were no serious adverse events, there were no infusion/injection site reactions, and no dose escalation stopping criteria were met. Plasma exposures of PF‐06741086 increased greater than proportionally with dose under the same dosing route. Coagulation pharmacology was demonstrated via total TFPI, dilute prothrombin time, D‐dimer, prothrombin fragment 1 + 2 and thrombin generation assay parameters.

Conclusions

Single doses of PF‐06741086 at multiple dose levels were safe and well tolerated in a healthy adult male population. The safety, PK and PD data from this study support progression to a multiple‐dose study in hemophilic patients.

     

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.     

Pharmacokinetics,safety, and tolerability of ceftolozane/tazobactam in healthy Japanese,Chinese, and white subjects

Ceftolozane/tazobactam, a novel antibacterial with potent activity against Gram‐negative pathogens, was developed for treatment of complicated urinary tract infections, including pyelonephritis, and intra‐abdominal infections. A phase 1 pharmacokinetic (PK) study of ceftolozane/tazobactam in healthy Japanese, Chinese, and white volunteers was conducted to assess the potential effect of ethnicity on PK. The PK of ceftolozane, tazobactam, and tazobactam metabolite M1 was compared after single 1.5‐ and 3‐g intravenous doses of ceftolozane/tazobactam. Ten Japanese, nine Chinese, and ten white subjects were enrolled, and 27 completed all doses of study medication. Dose‐normalized PK parameters for ceftolozane and tazobactam were similar among Japanese, Chinese, and white subjects (at 1.5‐g and 3‐g doses, ceftolozane area under the plasma concentration–time curve from zero to infinity [AUC_0–∞] = 166.3, 165.9, and 185.5 h μg/mL, respectively, and 157.7, 158.5, and 181.2 h μg/mL, respectively; tazobactam AUC_0–∞ = 48.5, 43.2, and 50.1 h μg/mL, respectively, and 47.3, 43.7, and 50.0 h μg/mL, respectively. The 90% CIs of their ratio estimates were within the range 0.80 to 1.25 with the exception of AUC_0–∞ for ceftolozane after the 3‐g dose (0.79). The cumulative amount of ceftolozane and tazobactam excreted in urine was similar among ethnic groups. For all groups, treatment‐emergent adverse events (AEs) were mild; no deaths or serious AEs were reported. The PK of ceftolozane/tazobactam was approximately dose proportional (i.e. doubling the dose approximately doubles the exposure) and similar among the groups. No dosage adjustment is needed for ceftolozane/tazobactam in Japanese and Chinese patients.     

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.     

Faecal bile acid analysis and intestinal absorption in Crohn''s disease before and after ileal resection

Abstract. Faecal bile acids were analysed by gas chromatography in 104 patients. Total bile acids exceeded 1.5 mmol/24 h in 33% of forty-five unoperated patients and in 90% of those having undergone an ileal resection. Lithocholic and deoxycholic fractions were lower in the unoperated patients than in the control group ( P < 0.05 and P < 0.005) and much lower after ileal resection than in unoperated patients ( P < 0.001). A significant correlation ( r = 0.58; P < 0.001) was found between total bile acids and relative proportions of primary bile acids in operated patients, untreated by antibiotics or sulfasalazine. Dihydroxy bile acids (predominantly chenodeoxycholic acid) correlated with faecal weight in unoperated patients ( r = 0.47, P < 0.01) and in 0–50 cm ( r = 0.69, P < 0.001) and 50–100 cm ( r = 0–63, P < 0.01) ileal resection groups. Our results suggest that the frequently altered bile acid composition is related to a shortening of colonic transit time which reduces the exposure of primary bile acids to bacterial 7α-dehydroxylase.     

Population pharmacokinetics of intravenous valproic acid in Korean patients

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.     

Pharmacokinetics,biocompatibility and bioavailability of a controlled release monoclonal antibody formulation

The sustained and localized delivery of monoclonal antibodies has become highly relevant, because of the increasing number of investigated local delivery applications in recent years. As the local delivery of antibodies is associated with high technological hurdles, very few successful approaches have been reported in the literature so far. Alginate-based delivery systems were previously described as promising sustained release formulations for monoclonal antibodies (mAbs). In order to further investigate their applicability, a single-dose animal study was conducted to compare the biocompatibility, the pharmacokinetics and the bioavailability of a human monoclonal antibody liquid formulation with two alginate-based sustained delivery systems after subcutaneous administration in rats. 28 days after injection, the depot systems were still found in the subcutis of the animals. A calcium cross-linked alginate formulation, which was injected as a hydrogel, was present as multiple compartments separated by subcutaneous tissue. An in situ forming alginate formulation was recovered as a single compact and cohesive structure. It can be assumed that the multiple compartments of the hydrogel formulation led to almost identical pharmacokinetic profiles for all tested animals, whereas the compact nature of the in situ forming system resulted in large interindividual variations in pharmacokinetics. As compared to the liquid formulation the hydrogel formulations led to lower mAb serum levels, and the in situ forming system to a shift in the time to reach the maximum mAb serum concentration (T_max) from 2 to 4 days. Importantly, it was shown that after 28 days only marginal amounts of residual mAb were present in the alginate matrix and in the tissue at the injection site indicating nearly complete release. In line with this finding, systemic drug bioavailability was not affected by using the controlled release systems. This study successfully demonstrates the suitability and underlines the potential of polyanionic systems for local and controlled mAb delivery.     

Hepatic uptake and intestinal absorption of bile acids in the rabbit

Abstract The existence of transporters for bile acids (BA) in liver and intestine has been well documented, but information is still needed as to their respective transport capacity. In the present investigation, we compared the hepatic and intestinal transport rates for BA, using perfused livers and intestines. The livers and intestines were separately perfused and dose-response curves (0·25–10 mM) for tauroursodeoxycholate, taurocholate and taurodeoxycholate were obtained. The intestinal and mesenteric concentration and bile acid pattern were also evaluated in six non-fasting rabbits. Taurocholic, tauroursodeoxy-cholic and taurodeoxycholic acid ileal absorption showed saturation kinetics in the intestine as in the liver; the maximal uptake velocity for each bile acid in the liver was tenfold higher than the respective maximal transport velocity in the intestine; the Km values obtained in the liver were of the same order of magnitude, i.e. in the millimolar range. Taurocholic, tauroursodeoxycholic and taurodeoxycholic acid transport differences in the liver paralleled those in the intestine. Although the intestine was not homogeneously filled, the bile acid concentration in the ileal content fell into the range of the Km for the three studied bile acids, while the portal blood total bile acid concentration was inferior to the observed Kms of liver uptake. Therefore, both the hepatic and intestinal systems do not operate at their maximal transport rates at the prevailing concentrations in portal blood and luminal content, and the hepatic transport occurs at its highest efficiency (below the Km values) in physiological conditions.     

Perioperative pharmacology: pharmacotherapeutics, pharmacokinetics, and pharmacodynamics

Results of current research into perioperative medication errors have revealed that more than half of medication errors occur during the administration phase of the medication-use process. The administration phase is the point at which the medication and the patient intersect and the medication imposes its pharmacological effect. During this phase, the only safety net between the patient and the medication is the health care provider's attention and care when administering the medication. To help mitigate these errors, perioperative nurses must understand pharmacotherapeutics: the use of medications to prevent, treat, cure, or alleviate symptoms of disease. Pharmacotherapeutics incorporates pharmacokinetics (ie, what the body does to a medication after it enters the system) and pharmacodynamics (ie, how a medication acts on the body to achieve a desired therapeutic effect).     

Determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates by means of stable isotope dilution technique, making use of deuterated cholic acid and chenodeoxycholic acid

A procedure is described for the simultaneous determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates. After oral administration of known amounts of 11,12-dideuterated chenodeoxycholic acid and 2,2,4,4-tetradeuterated cholic acid, the ratios of chenodeoxycholic acid-D2/chenodeoxycholic acid and cholic acid-D4/cholic acid are measured in consecutive serum samples, after which fractional turnover rates and pool sizes of chenodeoxycholic acid and cholic acid are determined arithmetically. In 7 healthy volunteers pool sizes for chenodeoxycholic acid and cholic acid were 22.9 +/- 7.8 and 24.1 +/- 11.7 mumol/kg, respectively. The corresponding values for the fractional turnover rates were 0.23 +/- 0.10 and 0.29 +/- 0.12/day. After oral administration of the labelled bile acids in capsule, the obtained pool sizes were significantly higher than after administration in a bicarbonate solution. Bile acid kinetics were also performed in a patient suffering from a cholesterol synthesis deficiency and in a patient very likely suffering from a bile acid synthesis deficiency. Furthermore, the kinetics of the intestinal absorption and hepatic clearance of unconjugated bile acids have been investigated in 2 healthy subjects.