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Transport and Metabolism in the Hepatobiliary System

Dirk K. F. Meijer

10.1002/cphy.cp060335

Source: Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Methodology
2 Factors Influencing Clearance of Drugs by The Liver
2.1 Chemical Structure
2.2 Protein Binding
2.3 Bile Flow
2.4 Adaptive Changes
2.5 Biotransformation, Detoxification, Toxification
2.6 Acinar Heterogeneity
3 Mechanisms Of Membrane Transport of Organic Compounds
3.1 General Considerations
3.2 Organic Anions
3.3 Organic Cations
3.4 Uncharged Compounds
4 Conclusion
Figure 1. Figure 1.

Ultrastructure of the liver. Scanning electron micrograph (x 5,000) showing the sinusoidal wall with large fenestrae and a plate of parenchymal cells (hepatocytes) with microvilli at the sinusoidal and canalicular poles of the cell representing sites for carrier‐mediated transport of drugs.
Figure 2. Figure 2.

Plasma disappearance and biliary excretion rate patterns after intravenous injection of 1,000 μg d‐tubocurarine (organic cation). Curve stripping of triexponential curves reveals almost identical slopes in plasma and bile, enabling calculation of transport rate constants for hepatic uptake and biliary excretion using compartmental models 40 as well as plasma and biliary clearance [cf. Fig. 4242].
Figure 3. Figure 3.

Relation between lipophilicity (measured by partition between octanol and Krebs buffer and expressed relative to the value of tetraethyl methylammonium) and carrier‐mediated clearance of 14 monovalent organic cations (drugs with a quaternary ammonium group) via biliary, intestinal, and renal routes in the rat. Clearance values are corrected for passive fluxes (e.g., glomerular filtration) and indicate carrier‐mediated transport in the organs. Between log P = 1 and log P = 2, biliary clearance increases ∼1,000 and intestinal clearance ∼100 times in contrast to renal clearance, which shows no such correlative pattern. At log P > 2.5, clearance is partly blood‐flow limited.
Figure 4. Figure 4.

Influence of albumin on clearance of dibromosulfophthalein (DBSP) in isolated perfused liver after single injection (A). Inverse relation is shown between albumin concentration and initial uptake rate. Lowering of albumin concentration increases unbound fraction and thereby the driving force for transport into the liver (hepatic storage) and liver to bile. B: influence of extracellular binding on hepatic storage of DBSP. Steady‐state kinetics by constant infusion of 800 nmol/min of DBSP in isolated rat liver perfused with 0.2% albumin containing Krebs solution. At t = 60 min, albumin was added to the perfusion medium to a concentration of 1.0%. Before addition, constant concentrations in bile, liver, and perfusate were attained. Addition of albumin results in disturbance of steady state and efflux of DBSP from the liver (C) to the perfusate plasma (B).
Figure 5. Figure 5.

Schematic representation of supposed mechanisms for organic anion transport at sinusoidal level. Net transport across the membrane is mediated by an undefined trans‐locator (carrier or ion‐selective channel protein) transporting the unbound substrate. At the plasma membrane surface, interaction of albumin may lead to facilitated dissociation of the organic anion (left). Alternatively, spontaneous dissociation by progressive removal of the unbound fraction may occur, in which dissociation from albumin may constitute the rate‐limiting step (right). Within the cell the substrate is associated with cytosolic‐binding proteins such as ligandin (glutathione transferase B) and Z protein (fatty acid–binding protein).

Adapted from Berk et al. 29
Figure 6. Figure 6.

Schematic representation of drug disposition by the liver. Hepatic uptake can occur passively or by carrier transport. Phase I and phase II biotransformation may produce polar conjugates that can be excreted into the general circulation or into bile, both via carrier‐mediated transport. Conjugates or polar drugs may also be excreted via tubular secretion in the urine or via intestinal secretion. In the gut, conjugates can be deconjugated and reabsorbed, undergoing enterohepatic cycling.
Figure 7. Figure 7.

Schematic representation of interrelation of phase I and phase II biotransformation reactions. Smooth endoplasmic reticulum (SER) membranes contain NADPH–cytochrome P‐450 reductase (Cyt. Red.) closely associated cytochrome P‐450, UDP‐glucuronosyltransferase (GIT), epoxide hydratase (EH), and a supposed permease (carrier, C) for UDPGA transport. Products of the monooxygenase are hydroxylated drug, drug epoxides, and reactive drug metabolites (radicals and electrophiles). The latter can undergo covalent binding to macromolecules in cell organelles, cytoplasm, and plasma membranes. Phase II synthetic reactions of, for example, phase I products include conjugation with glutathione (GSH) via the various glutathione S‐transferases (GST), sulfuric acid (SO3H) via the sulfotransferase (ST) using 3‐phosphoadenosine‐5'‐sulfate phosphate (PAPS), and glucuronic acid (GA) using UDPGA. Resulting polar conjugates are substrates for excretion mechanisms at sinusoidal and canalicular poles of the hepatocyte.
Figure 8. Figure 8.

Proposed scheme of the cytochrome P‐450 oxidation‐reduction cycle representing the monooxygenase, oxidase, and peroxygenase function. RH, xenobiotic compound; ROH, hydroxylated product. XOOH, formation of various peroxy compounds, including hydrogen peroxide.
Figure 9. Figure 9.

Graphic representation of the different forms of cytochrome P‐450 (circles) in the human with different, but probably overlapping, substrate and product selectivities. Arrows, single metabolic pathways. AM, aminopyrine; AP, antipyrine; BD, benzodiazepine; CF, caffeine; CMC, carboxymethylcysteine, DB, debrisoquine; ES, endogenous substrate; HB, hexobarbital; HP, heptabarbital; MB, methylphenobarbital; MP, mephenytoin; NF, nifedipine; NT, nortriptyline; PH, phenytoin; SP, sparteine; ST, steroid; TP, theophylline.
Figure 10. Figure 10.

Schematic representation of the microcirculatory unit of the liver: the hepatic acinus. An arbitrary division in 3 zones is indicated. BD, bile ductule; HA, hepatic artery; TPV, terminal portal venule.
Figure 11. Figure 11.

Light‐microscopic autoradiographs of rat liver 30 s after injection of [3H]taurocholate in rat liver perfused in normal direction (antegrade) and retrograde, using freeze autoradiography to prevent diffusion of the water‐soluble compound. Steep acinar gradients are observed in zone 1 and zone 3, respectively. Large black dots, material present in bile ducts at t = 30 s, which is only visible after antegrade perfusion. HV, hepatic venule; PV, portal venule.
Figure 12. Figure 12.

Taurocholate kinetics in isolated perfused livers after antegrade and retrograde perfusion. Plasma disappearance rate (distribution to the liver, left panel) is independent of direction of flow, whereas biliary excretion rate (right panel) is more rapid at normal direction of flow. Because distribution to zone 1 is predominant at normal flow (cf. Fig. 12, zone 1 cells may be better equipped for bile secretion of taurocholate than zone 3 cells.
Figure 13. Figure 13.

Chemical structure of cholephilic compounds for which separate transport processes have been proposed. However, indocyanine green (organic anion) contains also a cationic group. Cholic acid can be present as organic anion, as an undissociated carboxylic steroidal compound, or complexed with Ca2+ with a net positive charge. The steroid structure of ouabain (uncharged compound) resembles that of bile acids, and the organic cation d‐tubocurarine may form electroneutral ion pairs. These features enable multiple interactions and overlapping substrate specificity for transport systems.
Figure 14. Figure 14.

Calculated concentration gradients of unbound drug across sinusoidal and canalicular membranes for the organic anion dibromosulfophthalein (DBSP), the organic cation procaineamide ethobromide (PAEB), the uncharged compound ouabain (ouab), and the bile salt taurocholate (TCh). Concentrations of the unbound drugs were determined in ultrafiltrates of plasma and cytosol fraction of liver homogenates. Cytosol concentrations were corrected for contamination with plasma and bile.
Figure 15. Figure 15.

Coupling between gradients of inorganic ions with carrier‐mediated transport of organic anions (OA−), bile acids (BA−), organic cations (OC+), and uncharged compounds (UC) in the hepatocyte. Inorganic ion pumps include electrogenic NA+‐K+ exchange, Na+‐H+, OH−‐SO4− antiport (sinusoidal), and Cl−‐HCO3− antiport (canalicular). Na+‐coupled bile acid transport (1) and OH−‐OA− antiport (2) at the sinusoidal level and HCO3−‐OA− antiport at the canaliculi are anionic systems. Organic cations are taken up by system 1 and may share a transport system for uncharged compounds (2). In the latter system, ion‐pair formation may play a role; at the canalicular level antiport of organic cations with protons is tentatively assumed. Transport processes at sinusoidal level have more overlapping substrate specificity than the projected 4 canalicular carrier systems.

Adapted from Hugentobler and Meier 136
Figure 16. Figure 16.

Transport mechanisms for hepatobiliary transport of organic cations (OC+) within organelles and canaliculi is indicated by ☆. Uptake can occur by 2 systems. System 2 is inhibitable by cardiac glycosides that may share a carrier process transporting high‐molecular‐weight (bulky) lipophilic organic cations, possibly as ion pairs with inorganic counteranions. System 1 may preferentially serve monovalent cations and may operate by proton antiport. Lipophilic organic cations bind in plasma to α1‐acid glycoprotein (α1‐AGP) [orosomucoid (OR)] but are not coendocytosed with asialoforms of this glycoprotein (ASOR). Accumulation in lysosomes (L) may occur via aspecific fluid‐phase endocytosis at the plasma membrane or antiport with protons from the cytoplasm. Direct transport of drug from lysosomes to bile is not known. In addition to association with lysosomes, extensive binding can occur to mitochondria (M) and nuclei (N). Biliary excretion involves carrier‐mediated transport possibly by antiport with protons. Binding to mixed biliary micelles (Mi) may facilitate net transport into bile canaliculi. AGP‐rec., asialo‐glycoprotein receptor.


Figure 1.

Ultrastructure of the liver. Scanning electron micrograph (x 5,000) showing the sinusoidal wall with large fenestrae and a plate of parenchymal cells (hepatocytes) with microvilli at the sinusoidal and canalicular poles of the cell representing sites for carrier‐mediated transport of drugs.



Figure 2.

Plasma disappearance and biliary excretion rate patterns after intravenous injection of 1,000 μg d‐tubocurarine (organic cation). Curve stripping of triexponential curves reveals almost identical slopes in plasma and bile, enabling calculation of transport rate constants for hepatic uptake and biliary excretion using compartmental models 40 as well as plasma and biliary clearance [cf. Fig. 4242].



Figure 3.

Relation between lipophilicity (measured by partition between octanol and Krebs buffer and expressed relative to the value of tetraethyl methylammonium) and carrier‐mediated clearance of 14 monovalent organic cations (drugs with a quaternary ammonium group) via biliary, intestinal, and renal routes in the rat. Clearance values are corrected for passive fluxes (e.g., glomerular filtration) and indicate carrier‐mediated transport in the organs. Between log P = 1 and log P = 2, biliary clearance increases ∼1,000 and intestinal clearance ∼100 times in contrast to renal clearance, which shows no such correlative pattern. At log P > 2.5, clearance is partly blood‐flow limited.



Figure 4.

Influence of albumin on clearance of dibromosulfophthalein (DBSP) in isolated perfused liver after single injection (A). Inverse relation is shown between albumin concentration and initial uptake rate. Lowering of albumin concentration increases unbound fraction and thereby the driving force for transport into the liver (hepatic storage) and liver to bile. B: influence of extracellular binding on hepatic storage of DBSP. Steady‐state kinetics by constant infusion of 800 nmol/min of DBSP in isolated rat liver perfused with 0.2% albumin containing Krebs solution. At t = 60 min, albumin was added to the perfusion medium to a concentration of 1.0%. Before addition, constant concentrations in bile, liver, and perfusate were attained. Addition of albumin results in disturbance of steady state and efflux of DBSP from the liver (C) to the perfusate plasma (B).



Figure 5.

Schematic representation of supposed mechanisms for organic anion transport at sinusoidal level. Net transport across the membrane is mediated by an undefined trans‐locator (carrier or ion‐selective channel protein) transporting the unbound substrate. At the plasma membrane surface, interaction of albumin may lead to facilitated dissociation of the organic anion (left). Alternatively, spontaneous dissociation by progressive removal of the unbound fraction may occur, in which dissociation from albumin may constitute the rate‐limiting step (right). Within the cell the substrate is associated with cytosolic‐binding proteins such as ligandin (glutathione transferase B) and Z protein (fatty acid–binding protein).

Adapted from Berk et al. 29


Figure 6.

Schematic representation of drug disposition by the liver. Hepatic uptake can occur passively or by carrier transport. Phase I and phase II biotransformation may produce polar conjugates that can be excreted into the general circulation or into bile, both via carrier‐mediated transport. Conjugates or polar drugs may also be excreted via tubular secretion in the urine or via intestinal secretion. In the gut, conjugates can be deconjugated and reabsorbed, undergoing enterohepatic cycling.



Figure 7.

Schematic representation of interrelation of phase I and phase II biotransformation reactions. Smooth endoplasmic reticulum (SER) membranes contain NADPH–cytochrome P‐450 reductase (Cyt. Red.) closely associated cytochrome P‐450, UDP‐glucuronosyltransferase (GIT), epoxide hydratase (EH), and a supposed permease (carrier, C) for UDPGA transport. Products of the monooxygenase are hydroxylated drug, drug epoxides, and reactive drug metabolites (radicals and electrophiles). The latter can undergo covalent binding to macromolecules in cell organelles, cytoplasm, and plasma membranes. Phase II synthetic reactions of, for example, phase I products include conjugation with glutathione (GSH) via the various glutathione S‐transferases (GST), sulfuric acid (SO3H) via the sulfotransferase (ST) using 3‐phosphoadenosine‐5'‐sulfate phosphate (PAPS), and glucuronic acid (GA) using UDPGA. Resulting polar conjugates are substrates for excretion mechanisms at sinusoidal and canalicular poles of the hepatocyte.



Figure 8.

Proposed scheme of the cytochrome P‐450 oxidation‐reduction cycle representing the monooxygenase, oxidase, and peroxygenase function. RH, xenobiotic compound; ROH, hydroxylated product. XOOH, formation of various peroxy compounds, including hydrogen peroxide.



Figure 9.

Graphic representation of the different forms of cytochrome P‐450 (circles) in the human with different, but probably overlapping, substrate and product selectivities. Arrows, single metabolic pathways. AM, aminopyrine; AP, antipyrine; BD, benzodiazepine; CF, caffeine; CMC, carboxymethylcysteine, DB, debrisoquine; ES, endogenous substrate; HB, hexobarbital; HP, heptabarbital; MB, methylphenobarbital; MP, mephenytoin; NF, nifedipine; NT, nortriptyline; PH, phenytoin; SP, sparteine; ST, steroid; TP, theophylline.



Figure 10.

Schematic representation of the microcirculatory unit of the liver: the hepatic acinus. An arbitrary division in 3 zones is indicated. BD, bile ductule; HA, hepatic artery; TPV, terminal portal venule.



Figure 11.

Light‐microscopic autoradiographs of rat liver 30 s after injection of [3H]taurocholate in rat liver perfused in normal direction (antegrade) and retrograde, using freeze autoradiography to prevent diffusion of the water‐soluble compound. Steep acinar gradients are observed in zone 1 and zone 3, respectively. Large black dots, material present in bile ducts at t = 30 s, which is only visible after antegrade perfusion. HV, hepatic venule; PV, portal venule.



Figure 12.

Taurocholate kinetics in isolated perfused livers after antegrade and retrograde perfusion. Plasma disappearance rate (distribution to the liver, left panel) is independent of direction of flow, whereas biliary excretion rate (right panel) is more rapid at normal direction of flow. Because distribution to zone 1 is predominant at normal flow (cf. Fig. 12, zone 1 cells may be better equipped for bile secretion of taurocholate than zone 3 cells.



Figure 13.

Chemical structure of cholephilic compounds for which separate transport processes have been proposed. However, indocyanine green (organic anion) contains also a cationic group. Cholic acid can be present as organic anion, as an undissociated carboxylic steroidal compound, or complexed with Ca2+ with a net positive charge. The steroid structure of ouabain (uncharged compound) resembles that of bile acids, and the organic cation d‐tubocurarine may form electroneutral ion pairs. These features enable multiple interactions and overlapping substrate specificity for transport systems.



Figure 14.

Calculated concentration gradients of unbound drug across sinusoidal and canalicular membranes for the organic anion dibromosulfophthalein (DBSP), the organic cation procaineamide ethobromide (PAEB), the uncharged compound ouabain (ouab), and the bile salt taurocholate (TCh). Concentrations of the unbound drugs were determined in ultrafiltrates of plasma and cytosol fraction of liver homogenates. Cytosol concentrations were corrected for contamination with plasma and bile.



Figure 15.

Coupling between gradients of inorganic ions with carrier‐mediated transport of organic anions (OA−), bile acids (BA−), organic cations (OC+), and uncharged compounds (UC) in the hepatocyte. Inorganic ion pumps include electrogenic NA+‐K+ exchange, Na+‐H+, OH−‐SO4− antiport (sinusoidal), and Cl−‐HCO3− antiport (canalicular). Na+‐coupled bile acid transport (1) and OH−‐OA− antiport (2) at the sinusoidal level and HCO3−‐OA− antiport at the canaliculi are anionic systems. Organic cations are taken up by system 1 and may share a transport system for uncharged compounds (2). In the latter system, ion‐pair formation may play a role; at the canalicular level antiport of organic cations with protons is tentatively assumed. Transport processes at sinusoidal level have more overlapping substrate specificity than the projected 4 canalicular carrier systems.

Adapted from Hugentobler and Meier 136


Figure 16.

Transport mechanisms for hepatobiliary transport of organic cations (OC+) within organelles and canaliculi is indicated by ☆. Uptake can occur by 2 systems. System 2 is inhibitable by cardiac glycosides that may share a carrier process transporting high‐molecular‐weight (bulky) lipophilic organic cations, possibly as ion pairs with inorganic counteranions. System 1 may preferentially serve monovalent cations and may operate by proton antiport. Lipophilic organic cations bind in plasma to α1‐acid glycoprotein (α1‐AGP) [orosomucoid (OR)] but are not coendocytosed with asialoforms of this glycoprotein (ASOR). Accumulation in lysosomes (L) may occur via aspecific fluid‐phase endocytosis at the plasma membrane or antiport with protons from the cytoplasm. Direct transport of drug from lysosomes to bile is not known. In addition to association with lysosomes, extensive binding can occur to mitochondria (M) and nuclei (N). Biliary excretion involves carrier‐mediated transport possibly by antiport with protons. Binding to mixed biliary micelles (Mi) may facilitate net transport into bile canaliculi. AGP‐rec., asialo‐glycoprotein receptor.

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Article Title: Transport and Metabolism in the Hepatobiliary System
 

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Dirk K. F. Meijer. Transport and Metabolism in the Hepatobiliary System. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 717-758. First published in print 1989. doi: 10.1002/cphy.cp060335