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D K Meijer

Publications and source records attributed to D K Meijer.

At least 181 records · Page 10Linked to original sources
PubMed1986

alpha-Bromoisovalerylurea as model substrate for studies on pharmacokinetics of glutathione conjugation in the rat. II. Pharmacokinetics and stereoselectivity of metabolism and excretion in vivo and in the perfused liver.

The hypnotic drug alpha-bromoisovalerylurea (BIU) has been studied in the rat with respect to its potential use as model substrate to investigate the pharmacokinetics of glutathione conjugation in vivo. The major metabolites of racemic BIU are the diastereomeric glutathione conjugates (bile) and mercapturates (urine). BIU was metabolized mainly by glutathione conjugation: after i.v. administration of [14C]BIU to freely moving rats, 89% of the dose was recovered in urine within 24 hr, mostly as mercapturates. The rate-limiting step in the clearance of BIU from blood most likely is glutathione conjugation as it was shown that rate-limitation is not due to flow-limited clearance in the liver (the initial extraction ratio of BIU in the perfused liver preparation was low: hepatic extraction ratio = 0.23), protein binding (60% was unbound in plasma) or enzyme saturation (linear pharmacokinetics in the dose range studied: 22-270 mumol/kg). Water solubility of BIU was sufficient to allow its i.v. administration, whereas the absence of toxic effects enables animal as well as human studies. Thus, BIU is a promising model substrate for studies of glutathione conjugation in vivo. In pentobarbital-anesthetized rats with a bile duct catheter, equal amounts of metabolites were excreted in bile (almost exclusively as the two diastereomeric BIU glutathione conjugates) and urine (mostly as the two diastereomeric mercapturates). Based on similar experiments with bile duct-ligated rats, it was concluded that the appearance of the mercapturates in urine could also occur without biliary excretion and subsequent gut metabolism of the BIU glutathione conjugates. The ability of the liver to metabolize BIU was studied in a hemoglobin-free, recirculating liver perfusion system. Of the recovered radioactivity 40% was excreted in bile within 2 hr, almost exclusively in the form of the two BIU glutathione conjugates. Also, glutathione conjugates were found in the perfusate (16% of the radioactivity present in the perfusate after 2 hr). A distinct stereoselectivity was observed in the metabolite excretion rates. The excretion half-lives of the two diastereomeric glutathione conjugates in bile differed 2- to 3-fold, both in anesthetized rats and in the perfused liver preparation. A similar difference in excretion half-lives was found for the urinary excretion of the diastereomeric mercapturates. Thus, BIU can be used to investigate in vivo the stereoselectivity of glutathione conjugation.

Animals↗
PubMed1985

Measurement of the association of cholephylic organic anions with different binding proteins.

The binding of the colored cholephylic anions tetrabromosulfonphthalein (BSP), di-bromosulfonphthalein (DBSP), indocyanine green (ICG) and thymol blue (ThB) to a number of protein preparations including bovine serum albumin, human serum, rat hepatic cytosol and purified rat liver bilitranslocase has been studied by a direct spectrophotometric method. The experimentation provides extinction coefficients, dissociation constants and number of binding sites for the different complexes between dyes and the various proteins. Data obtained by this technique were in excellent agreement with those obtained on the same samples by ultrafiltration. The data presented indicate that the direct spectrophotometry applied to these dyes is simple, rapid and reproducible, making this the approach of choice during the purification of binding proteins when the binding capacity is the only useful criterion to follow the progress of the procedure.

Animals↗
PubMed1985

Secretion of the organic anion harmol sulfate from liver into blood. Evidence for a carrier-mediated mechanism.

In the liver, drugs with phenolic groups can be converted to sulfate or glucuronide conjugates and are then transported into bile or back into the bloodstream. The mechanism for transport of drugs and drug conjugates from the hepatocytes into the blood at the sinusoidal side of the cell are not well defined. In the case of carrier-mediated transport of these strongly polar conjugates, saturability of transport and mutual competition between structurally related compounds would be anticipated. This competitive aspect was investigated by using two organic anions, dibromosulfophthalein (DBSP) and harmol sulfate. The latter compound was generated by the hepatocytes from harmol, which was continuously infused into the rat in vivo and in isolated perfused rat livers. In addition we loaded the perfused rat livers with preformed harmol sulfate and studied its efflux rate to the perfusate as influenced by DBSP. In steady state, about 80% of harmol was sulfated and 20% was glucuronidated. Harmol sulfate was mainly excreted in the urine, the glucuronide was equally excreted in urine and bile. DBSP lowered the urinary excretion of harmol sulfate by about 30% which was due to a decrease in plasma concentration. However, renal clearance of harmol sulfate (3.2 +/- 0.2 ml/min) was unchanged. At the same time DBSP doubled the biliary clearance of harmol sulfate (1.0 +/- 0.1 and 2.2 +/- 0.2 ml/min in controls and DBSP studies respectively). DBSP decreased glucuronide excretion both in urine and bile. The increase in biliary output and decrease in urinary excretion of harmol sulfate is explained by competitive interaction between the organic anion DBSP and harmol sulfate at the sinusoidal level. Efflux experiments in single pass perfused isolated livers showed a clear decrease of harmol sulfate transport from liver into plasma by DBSP and provided evidence for such an inhibitory phenomenon (t 1/2 of efflux was 3.58 +/- 0.21 compared with 2.46 +/- 0.07 min for controls). These results indicate that organic anion transport from the hepatocyte into the blood stream is very likely carrier-mediated. A decrease in renal output of drug conjugates therefore may not only be due to a decrease in the conjugation process but also to a lower liver to blood transport rate which at the same time may produce a higher biliary output.

Alkaloids↗
PubMed1985

Biliary excretion of FITC metabolites after administration of FITC labeled asialo orosomucoid as a measure of lysosomal proteolysis.

An isolated perfused rat liver system was used to study the hepatic uptake and degradation of asialo orosomucoid (asialo alpha 1-acid glycoprotein). To this aim we coupled the fluorochrome FITC to the asialoglycoprotein. The covalent attachment of FITC to the glycoprotein did not affect its perfusate disappearance. The disappearance rate was characterized by a t1/2 approximately equal to 6.1 min, the clearance being 11.2 ml/min. The internalized ligand was probably extensively degraded in the lysosomes as demonstrated by the appearance of low molecular weight fluorescent compounds in the bile, having a higher fluorescence yield than the native conjugate. Lysosomal degradation of ASOR-FITC was shown to be the rate limiting step in FITC excretion into the bile. Treatment of a perfused liver with varying doses of the protease inhibitor leupeptin did not influence the perfusate disappearance rate of the protein. However, leupeptin inhibited the biliary output of FITC metabolites in a dose dependent fashion, half maximal inhibition occurring at 210 nM (in the perfusion medium), corresponding with a dose of 0.05 mg leupeptin per 10 g liver. It is concluded that the rate of lysosomal degradation of proteins in vivo can be determined by measuring the biliary excretion of fluorescent material originating from fluorescent probes covalently coupled to the particular protein.

Animals↗
PubMed1985

Drastic improvement in the rectal absorption profile of morphine in man.

Rectal absorption of morphine HCl from aqueous vehicles at different pHs in man has been compared with an orally administered solution. Plasma concentrations of morphine were measured by electrochemical HPLC analysis after a single dose of 10 mg morphine HCl, in a cross-over study in 7 volunteers. Rectal absorption of morphine was dependent on pH, which could be explained as being due to pH partitioning. The absorption rate and bioavailability could be greatly improved, as compared to orally administered morphine, by adjusting the pH. It was concluded that a rectal solution adjusted to pH 7 to 8 provided an entirely adequate dosage form.

Administration, Oral↗
PubMed1985

Binding of drugs with a quaternary ammonium group to alpha-1 acid glycoprotein and asialo alpha-1 acid glycoprotein.

The interaction of eight mono- and four bisquaternary ammonium compounds with alpha-1 acid glycoprotein and its desialylated derivative was investigated. Protein binding was performed in vitro by equilibrium dialysis at 37 degrees C. The simple monoquaternary ammonium compounds tributylmethylammonium, tripropylmethylammonium, triethylmethylammonium and procainethobromide were not appreciably bound (unbound fraction greater than 0.99). Excellent negative correlations of unbound fraction and the log of the octanol/Krebs' partition coefficient were obtained for thiazinamium, N-methylimipramine, N-methyldeptropine and d-tubocurarine, both for alpha-1 acid glycoprotein (r = -0.99) and asialo alpha-1 acid glycoprotein (r = -0.94). Bisquaternary ammonium compounds, with the exception of hexafluorenium, were only poorly bound. Our binding data on N-methyl-deptropine, N-methylimipramine and thiazinamium reveal that these compounds are more avidly bound to alpha-1 acid glycoprotein than to albumin, in spite of their polar character. The interaction of N-methyldeptropine with alpha-1 acid glycoprotein was studied in more detail. Scatchard plots revealed the presence of two classes of binding sites. N-Methyldeptropine could effectively be displaced by imipramine from its high-affinity binding site. This points to the presence of a common high-affinity binding site for tertiary and quaternary ammonium compounds on alpha-1 acid glycoprotein.

Asialoglycoproteins↗
PubMed1984

Hepatic uptake and biliary excretion of organic cations--I. Characterization of three new model compounds.

Three quaternary ammonium compounds (QACs) with different lipophilicity, triethylmethyl ammonium iodide (TEMA), tripropylmethyl ammonium iodide (TPMA) and tri-n-butylmethyl ammonium iodide (TBuMA) were given as a bolus injection of 10 mumole and 1 mumole in an isolated perfused liver. TPMA and TBuMA exhibited saturation kinetics at a dose of 10 mumole, but not when 1 mumole of the agents was given. Biliary clearance of TEMA was equal to the bile flow (0.010 ml/min), whereas for TPMA and TBuMA much higher values of 0.8 ml/min and 2.2 ml/min were found respectively. Partition coefficients of TEMA, TPMA and TBuMA between n-octanol and Krebsbicarbonate solution were 0.0013, 0.013 and 0.14 respectively. Liver-to-plasma concentration ratios were 4, 16 and 30 in the post-distribution phase, whereas bile-to-liver ratios were calculated to be 0.1, 1.3 and 14 respectively. The latter parameter varied roughly proportionally to the lipophilicity of the compounds. The liver/plasma concentration ratios corrected for intracellular binding exceeded a value of 12 indicating that accumulation in the liver of these agents cannot soley be explained by passive equilibration according to the membrane potential. Transport from liver into the bile of TPMA and TBuMA presumably also occurred against an electrochemical gradient. It was inferred that the small molecular weight compounds such as TEMA, can be transported from plasma into bile paracellularly by a passive process. Rapid uptake into the liver of such compounds may not lead to an appreciable biliary output and can even reduce the rate of biliary excretion. QACs with intermediate or high lipophilicity are transported by carrier mediated processes both at the level of hepatocyte uptake and bile canalicular transport. The influence of choleresis on hepato-biliary transport of the three QACs was investigated by giving sodium taurocholate (Tc) by constant infusion of 60 mumole/hr, increasing bile flow from 9 to 16 microliter/min. The biliary output of TEMA appeared to be basically unaffected, whereas the biliary excretion of TPMA and TBuMA was clearly elevated when the bile flow was increased. The stimulatory influence of taurocholate on the biliary output of the latter organic cations is explained by an increased net uptake of these agents into the liver and an increased net canalicular transport. This effect is proposed to be due to a reduced reabsorption from the biliary tree as a consequence of the higher bile flow and/or biliary micelle binding. Taurocholate increased liver-to-plasma ratios.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Hepatic uptake and biliary excretion of organic cations--II. The influence of ion pair formation.

The influence of an anorganic anion iodide (I-) and an organic anion tetraphenylborate (TPB-) on the hepatic uptake and biliary excretion of three organic cations, triethylmethyl ammonium (TEMA), tripropylmethyl ammonium (TPMA) and tri-n-butylmethyl ammonium (TBuMA) was studied. The compounds were injected as a bolus (D = 1 mumole) and studied in isolated perfused livers. In the perfusion medium 25% of the amount of NaCl (3 mmole) was replaced by NaI, whereas in two other experiments TPB- was added to the medium in two concentrations (2 microM and 200 microM). NaI did not affect the biliary output of the three quaternary ammonium compounds (QACs) although an increased net rate of hepatic uptake was found for all compounds, most likely due to a decreased liver to plasma transport. Liver to plasma concentration ratios were increased, while the ratios between bile to liver and bile to plasma were not affected. TPB- in catalytic amounts added to the medium (2 microM) decreased the biliary output of TEMA and TBuMA, whereas the kinetic profile of TPMA was unchanged. The decreased biliary excretion rate of TEMA was explained by a decreased plasma level (due to the increased liver uptake) assuming that the small molecular weight compounds can enter the bile directly from plasma via the junctional complexes between the cells. The bile to plasma (B/P) ratio was not affected. In contrast, the bile to plasma (B/P) ratio and the bile to liver (B/L) ratio of TBuMA were decreased, compared with the control, probably due to an increased reabsorption from the bile, whereas the back transport from the liver into the plasma was also decreased. A large amount of TPB- (200 microM), added to the perfusion medium, dramatically changed the kinetic profile of the three QACs. Ion pair formation between the QACs and TPB- was supposed to be responsible for this effect. Plasma levels dropped more rapidly as a result of an increased rate of liver uptake. The biliary excretion of all compounds was greatly reduced (the excretion rates were 0.022, 0.19 and 0.18 nmole/min, compared with 0.047, 0.71 and 7.5 nmole/min for the controls). It is concluded that ion pair formation may play a role in the hepatobiliary transport. The rate of liver uptake of the QACs is enhanced in the presence of an anion, which is due to an increase in plasma to liver transport (k12) and a reduced liver to plasma transport (k21).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Preliminary study on the absorption profile after rectal and oral administration of methadone in human volunteers.

Methadone is a potent, long acting narcotic analgesic which can be orally administered due to its almost complete bioavailability. There is a growing interest in the rectal route of administration in the case of acute post-operative or chronic malignant pain. Since virtually no data were available on the rectal absorption profile of methadone in man, plasma concentrations of methadone were determined by means of HPLC analysis after a single dose of 10 mg methadone HCl in a cross-over pilot study in five volunteers. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. Compared with oral dosing, the extent of rectal absorption from an aqueous solution was almost 80% up to 8 h after dosing. Although the mean peak concentration and the AUC0-8h was significantly lower (p less than 0.01), no marked difference in tmax was observed: 2.8 and 3.1 h respectively. Rectal absorption conditions of methadone from fatty suppositories (3 ml) were found to be less favourable. The peak plasma concentration was only reached 3-4 h after administration, whereas the relative bioavailability up to 8 h after dosing ranged from 35-58%. This rate-limiting absorption pattern may be due to the critical solubility properties of methadone HCl at physiological pH.

Administration, Oral↗
PubMed1984

Rectal absorption of metronidazole from polyethylene glycol suppositories.

The rectal absorption of metronidazole from an aqueous suspension, a fatty suppository and three different polyethylene glycol suppositories was studied in healthy volunteers and compared with absorption from an oral solution. Rectal absorption was found to be rather slow for all suppositories. Of all rectal dosage forms, the polyethylene glycol suppositories gave the highest peak plasma levels and the highest relative bioavailability. Compared with oral administration, a relative bioavailability of 80% could be obtained.

Administration, Oral↗
PubMed1984

Lumen perfusion of the human rectum in situ: a method to study mechanisms for rectal drug transport in humans.

A lumen perfusion system was developed to study rectal transport mechanisms in humans. With this technique it is possible to perfuse a well-defined area of the rectum wall under single-pass and recirculation conditions. Sodium benzoate was used as a test drug. After absorption, sodium benzoate is conjugated with glycine to give hippuric acid which is rapidly eliminated (t 1/2 = 0.5 h). Due to the short half-life it is possible to reach a steady-state concentration within 2.5 h of perfusion. Plasma concentrations of hippuric acid were determined by HPLC. The absorption influx of sodium benzoate per unit area (phi in) could be calculated using the steady-state concentration of hippuric acid during rectal perfusion, the separately measured total body clearance after intravenous injection, and a designated absorption surface of the rectum. It was shown that with this technique reproducible phi in values within one subject could be obtained. Four volunteers were perfused with four different solutions of sodium benzoate, and it was found that phi in was proportional to the four concentrations used. In the case of recirculation perfusion (two volunteers), it was found that the amount of the perfusate lost equalled the amount absorbed into the general circulation. Therefore, the possibility of major drug accumulation in the rectal lumen or mucosa could be excluded. The perfusion technique elaborated in the present study can be used to investigate the mechanism of rectal absorption in humans as well as the factors that may influence this process.

Benzoates↗
PubMed1984

Structure-pharmacokinetics relationship of quaternary ammonium compounds. Elimination and distribution characteristics.

The pharmacokinetics of a series of fourteen monoquaternary ammonium ions, with gradually increasing molecular weight, were studied in anaesthetized rats after intravenous bolus injection and/or constant infusion. Distribution to the eliminating organs and elimination rate into bile, urine and intestinal lumen as well as the plasma disappearance were investigated. All compounds showed a double exponential plasma disappearance pattern. Initial half lives (alpha-phase) varied between 0.5 and 3 min, half lives of the beta-phase varied between 30 and 70 min. Total plasma clearance within the series of compounds ranges from 2.3-13.7 ml/min, in general increasing with molecular weight. The relative contribution of biliary, urinary, and intestinal elimination to the total plasma clearance varied widely within the series of organic cations. Renal clearance of all the compounds exceeded that of mannitol, indicating involvement of active renal transport processes. Excretion via the kidneys was the only important excretory pathway for compounds with molecular weights less than 156. The low biliary excretion of the compounds of M less than 156 was not due to a deficient hepatic penetration since uptake into the liver was very rapid. Only the high molecular weight compounds (greater than 156) showed a profound bile/plasma concentration ratio ranging from 13 to 830. For these compounds also an "uphill" excretion process into the gut lumen seems to be involved representing up to 15% of the administered dose. It is concluded that elimination patterns for organic cations of various structure differ much more than their overall distribution characteristics.

Animals↗
PubMed1984

Structure-pharmacokinetics relationship of quaternary ammonium compounds. Correlation of physicochemical and pharmacokinetic parameters.

Correlations between lipophilicity or molecular weight and some pharmacokinetic parameters such as clearance (Cl), elimination rate constant (k10), volume of distribution (V), and terminal half life (lambda z) are presented for a series of structurally related quaternary ammonium cations (QACs). The structure-pharmacokinetics relations were fitted using the computer program NONLIN and were represented by linear, parabolic or S-shaped curves. The relationship between total plasma clearance or hepatic, renal and intestinal clearance and lipophilicity for the present set of data could be described most properly by the equation Y = 1/(aXb + c), where Y stands for the logarithm of the pharmacokinetic parameters and X represents the logarithm of the values of some physicochemical parameters, such as the partition coefficient (P), the (HPLC) capacity factor k' (another lipophilicity parameter) and molecular weight (MW). On the basis of this relationship, correlations of the hepatic or intestinal clearances with the lipophilicity parameters were good (r = 0.98 and r = 0.95 respectively). Curves relating values for partition coefficients and clearance via liver and intestine (expressed relative to the most simple QAC tetramethyl ammonium) showed S-shaped correlation patterns, in contrast to the renal clearance, which correlated poorly (r = 0.54) with lipophilicity. The extent of biliary output of the organic cations shows a threshold phenomenon, sharply increasing at log P greater than 1.5 to a maximum at P greater than 2.5. This pattern was less pronounced in the case of intestinal elimination and absent in the case of renal clearance. The apparent maximum in the hepatic and intestinal clearance for the most lipophilic organic cations is probably due to limitation by organ blood-flow and/or plasma protein binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Pharmacokinetics of the oral narcotic analgesic bezitramide and preliminary observations on its effect on experimentally induced pain.

The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5-1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5-3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n = 6, 3H-bezitramide 2.5 micrograms), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.

Adult↗
PubMed1984

Pharmacokinetics of the hepatic transport of organic anions: influence of extra- and intracellular binding on hepatic storage of dibromosulfophthalein and interactions with indocyanine green.

The influence of intracellular and extracellular protein binding on the hepatic storage and biliary elimination of dibromosulfophthalein (DBSP) was studied in isolated perfused rat liver. Under first order kinetic conditions the amount of DBSP in the liver at a given plasma concentration (hepatic storage) was determined by extracellular binding to albumin and intracellular binding to the cytosolic Y and Z proteins as well as concentrative membrane transport from plasma into the liver. At higher doses, extensive binding of DBSP to intracellular organelles also occurred while liver cytosol/plasma concentration gradients of unbound DBSP were much lower. Hepatic storage increased with decreasing albumin concentration in the perfusate of isolated perfused rat livers. However, it was shown that this parameter is dose-dependent, and errors can be introduced in its calculation if nonlinearity of sinusoidal and canalicular transport processes as well as nonlinear protein binding are not taken into account. The influence of another organic anion, indocyanine green (ICG) on the hepatic storage, subcellular distribution, and elimination of DBSP was subsequently studied. At equimolar amounts the presence of ICG resulted in a 50% decrease in hepatic clearance and hepatic distribution volume of DBSP. It was inferred that these changes are due to an inhibition of carrier-mediated transport across the sinusoidal and canalicular membrane and preferential displacement from intracellular binding sites. In contrast DBSP in equimolar amount enhanced the initial disappearance rate and biliary excretion of ICG, probably due to increasing its free fraction in plasma. It is concluded that the level and mechanism of interaction of two drugs within the eliminating organ can be characterized by combining clearance studies with data on subcellular and extracellular binding.

Animals↗
PubMed1983

Acinar heterogeneity in hepatic transport of dibromosulfophthalein and ouabain studied by autoradiography, normal and retrograde perfusions and computer simulation.

This study is aimed to investigate the relative involvement of periportal (zone 1) and perivenous (zone 3) hepatocytes in the uptake and biliary excretion of the organic anion dibromosulfophthalein (DBSP) and the uncharged cardiac-glycoside ouabain. The localization in the acinus of [35S]BSP (sulfobromophthalein, the tetra-bromo-analogue of DBSP) and [3H]ouabain administered to livers perfused with normal and retrograde flow, was detected by autoradiography. The plasma disappearance and biliary excretion rates of DBSP and [3H]ouabain were determined in normal and retrograde perfusions. In addition, computer simulations were performed to predict the effect of reversal of the perfusate flow on the plasma disappearance and biliary excretion rate curves and on the concentration of label in zones 1 and 3. Autoradiography showed that 2 and 10 min after injection of [35S]BSP to normally and retrogradely perfused livers, the label was uniformly distributed in the liver acinus. The same results were found 30 sec and 10 min after injection of [3H]ouabain to normally and retrogradely perfused livers. The plasma disappearance and biliary excretion rate of DBSP were slightly faster in retrograde perfusions compared to normal perfusions both with and without a basal bile salt infusion of 15 mumole/hr. This could not be explained by an acinar heterogeneity with respect to any of the DBSP transport steps (plasma to liver, liver to plasma, liver to bile) as was shown by computer simulations. The plasma disappearance and biliary excretion rate of ouabain were similar in normal and retrograde perfusions. It is concluded that periportal and perivenous hepatocytes are equally involved in the uptake of (D)BSP and ouabain from the medium. However, due to the particular distribution patterns no conclusions can be drawn from normal and retrograde perfusions about the relative involvement of these cells in biliary excretion, as was shown by computer simulation. The unaffected kinetic behaviour of the retrogradely perfused livers indicated that no liver damage occurs during retrograde perfusion with respect to transport function.

Animals↗
PubMed1983

Heterogeneity of rat hepatocytes in transport and hepatic binding of asialoalkaline phosphatase studied after induction of selective acinar damage by N-hydroxy-2-acetylaminofluorene and carbon tetrachloride.

In order to investigate rat hepatocyte heterogeneity in asialoglycoprotein transport, rats were pretreated with N-hydroxy-2-acetylaminofluorene (N-OH-AAF, 90 mumol/kg, i.v.) to damage zone 1 hepatocytes, or with carbon tetrachloride (CCl4, 2.1 mmole/kg, p.o.) to damage zone 3 hepatocytes. Twenty-four hours after pretreatment, the asialoglycoprotein dog intestinal alkaline phosphatase (As-ALPase) was injected and plasma disappearance and biliary excretion were measured. In addition, the acinar distribution of the hepatic binding of As-ALPase 10 min after injection in vivo, or after incubation of fixed liver sections with As-ALPase in vitro, was determined by enzyme histochemistry. In control rats, a rapid biexponential plasma disappearance was observed and 6.4 +/- 1.5% of the dose was excreted into bile after 60 min. Hepatocyte binding occurred predominantly in zone 3, both after administration in vivo and after incubation with liver sections in vitro. In rats with zone 1 liver damage, both the half-lives of the first and of the second phase were strongly increased, but biliary excretion did not change significantly. Both in vivo and in vitro the relatively weak binding of As-ALPase in zone 1 of the liver was abolished, whereas binding to zone 3 cells was normal or only slightly decreased. After CCl4-pretreatment histochemically detectable binding to zone 3 cells was completely abolished, leaving only the relatively weak binding in zone 1. Unexpectedly, a normal plasma disappearance and biliary excretion rate were found in these rats. The discrepancy between the pharmacokinetic results, which point to a predominant involvement of zone 1 cells in As-ALPase transport, and the enzyme histochemical studies, which show preferential binding of As-ALPase in zone 3, is discussed.

2-Acetylaminofluorene↗