Mechanisms of Bile Secretion

Bräuer, Ralph W.

doi:10.1001/jama.1959.03000300058011

Cited by 113 publications

(31 citation statements)

References 6 publications

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“…The volume of biliary fluid is very small, resulting in very high drug concentrations and bile/plasma concentration ratios greater than 1, but most commonly between 10 and 1000 (37). Thus, passive transport of compounds is negligible and hepatobiliary elimination requires efflux transporters to move compounds from hepatocytes into the canalicular space.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

Yang

Gandhi

Duignan

et al. 2009

AAPS J

108

101

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Abstract. The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure-pharmacokinetic relationships (QSPKR) to predict biliary clearance (CL b ) and percentage of administered dose excreted in bile as parent drug (PD b ) in rats and humans. CL b and PD b data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PD b . Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PD b for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CL b showed a significant correlation (R 2 =0.819) with good prediction performance (Q 2 =0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CL b in rats and PD b data for anions or cation/neutral compounds in rats and humans. Both CL b and PD b data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.

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Section: Discussionmentioning

confidence: 99%

Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

Yang

Gandhi

Duignan

et al. 2009

AAPS J

108

101

View full text Add to dashboard Cite

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“…These results, when coupled with the relatively low concentrations of drug in the blood usually obtained with nitrofurantoin and its short half-life in blood, explain at least partially why significant biological drug residues have not been encountered with nitrofurantoin under clinical conditions (Conklin & Hailey, 1969;. Brauer (1959) divided substances which are excreted in bile into three groups on the basis of their bile to blood drug concentration ratios. According to Brauer (1959) and other recent reviewers (Smith, 1966;Stowe & Plaa, 1968), substances with bile to blood ratios of 10-1,000 usually require some active secretory process fo-r their transport from blood to bile.…”

Section: Discussionmentioning

confidence: 99%

“…Brauer (1959) divided substances which are excreted in bile into three groups on the basis of their bile to blood drug concentration ratios. According to Brauer (1959) and other recent reviewers (Smith, 1966;Stowe & Plaa, 1968), substances with bile to blood ratios of 10-1,000 usually require some active secretory process fo-r their transport from blood to bile. Characteristically these substances compete for transport, and their transport mechanism can be saturated by excess compound (Smith, 1966;Stowe & Plaa, 1968).…”

Section: Discussionmentioning

confidence: 99%

Excretion of nitrofurantoin in dog hepatic bile

Conklin

Wagner

1971

British J Pharmacology

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Summary After the intravenous administration of nitrofurantoin sodium to dogs at nitrofurantoin doses of 1·5–24·0 mg/kg, a substantial amount of nitrofurantoin is excreted in bile. The bile to blood drug ratios were about 200. A marked hydrocholeretic effect which correlated directly with the amount of nitrofurantoin administered was also observed. The excretion of nitrofurantoin in bile and the hydrocholeretic effect were linear with the dose of drug over the range 1·5–12·0 mg/kg. Maximum increases in hepatic bile flows were usually from 5–10 ml/0·5 h, while average control bile flow was 1·6 ml ± s.d. 0·6/0·5 hours. The lowest dose at which the hydrocholeretic effect was still detectable was 0·09 mg/kg. Apparent saturation of the biliary excretion system for nitrofurantoin and the hydrocholeretic mechanism occurred after a dose of 24·0 mg/kg. Saturation of the urinary system for nitrofurantoin excretion was noted after a dose of 6·0 mg/kg. Biliary nitrofurantoin recoveries ranged from 16·5% ± s.d. 4·2 to 22·6% ± s.d. 4·7 for the 6 h period after doses of 1·5, 30, and 6·0 mg/kg. Urinary nitrofurantoin recoveries for the same interval ranged from 24·1% ± s.d. 6·6 to 36·2% ± s.d. 8·3. In comparison to values obtained in normal dogs, only about one‐tenth of the drug excretion in bile and about one‐fifth of the hydrocholeretic effect were obtained after intravenous drug administration to dogs with hepatic impairment induced by CCl4.

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“…In addition, as a part of this process, concentration gradients would be established which would favor the movement of other solutes into the bile by passive diffusion. Among the latter solutes would be that group of substances which Cook, Lawler, Calvin and Green have referred to as "unconcentrated" (23) and which Brauer has characterized as appearing in bile "in concentrations closely reflecting those of plasma" (24). An additional quantity of water would have to accompany these solutes for the maintenance of normal osmolality.…”

Section: Effect Of Acetazolamidementioning

confidence: 99%