Rectal absorption of codeine phosphate from various dosage forms was studied in man. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. The plasma concentrations of codeine were measured by means of HPLC analysis after a single dose of 60 mg codeine phosphate in a cross-over study in 7 volunteers. Compared with oral dosing rectal absorption from an aqueous solution or a fatty suppository produced an almost identical plasma concentration profile with similar interindividual variations. Comparing the absorption rate characteristics it appeared that rectal absorption from an alkaline solution containing codeine phosphate proceeded significantly (P less than 0.05) more rapid than after oral dosing. No essential difference in bioavailability was observed between the various rectal and oral dosage forms.

Administration, Oral↗

PubMedDate not supplied

Drug targeting to the liver with lactosylated albumins: does the glycoprotein target the drug or is the drug targeting the glycoprotein?

The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drug-carrier conjugate fluorescein-lactosylated albumin (F-LnHSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactose-terminated glycoproteins. Clearance experiments with fluoresceinated 125I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (approximately 90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein per mole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of "inversed targeting" could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.

Animals↗

PubMedDate not supplied

Lactosylation of albumin reduces uptake rate of dibromosulfophthalein in perfused rat liver and dissociation rate from albumin in vitro.

Two types of models have recently been proposed to describe hepatic uptake kinetics of protein bound drugs: a model in which dissociation from plasma protein is rate limiting the process, and a model in which an interaction between protein and hepatocyte surface is thought to promote dissociation and uptake of the drug. This study was designed to investigate several aspects of both models, using lactosylated albumin as a binding protein that can interact with the Ashwell receptor abundantly present on the hepatocyte. Dibromosulfophthalein clearance was studied in rat liver in the presence of 150 microM (1%) albumin or 150 microM lactosylated albumin. Initial disappearance rate from perfusate in the presence of lactosylated albumin indicated a 2-fold decrease in hepatic uptake rate compared with native albumin. This was confirmed by compartmental analysis, showing a similar decrease in hepatic uptake rate constant. Protein binding of dibromosulfophthalein to lactosylated albumin was only marginally different from normal albumin. Consequently, modification of the protein retarded uptake of the organic anion at an essentially unchanged unbound concentration. Fluorescence spectroscopy of lactosylated albumin showed a blue-shifted tryptophan emission spectrum compared with albumin, indicating increased hydrophobicity of the neoglycoprotein. We therefore considered a change in off-and-on rate for binding of dibromosulfophthalein in lactosylated albumin. Rapid filtration experiments indicated that the dissociation rate constant of dibromosulfophthalein from lactosylated albumin was half that of controls. We conclude that the decreased off-rate from lactosylated albumin can explain the retarding influence on hepatic uptake rate of dibromosulfophthalein. This observation argues for the concept of dissociation-limited uptake in the hepatic clearance of the organic anion.

Animals↗

PubMedDate not supplied

Acinar redistribution and heterogeneity in transport of the organic cation rhodamine B in rat liver.

We studied a possible acinar heterogeneity in the transport of organic cations, using rhodamine B as model compound. Employing perfusions of isolated rat livers in the ante- and retrograde mode and quantitative fluorescence microscopy, Zones 1 and 3 were shown to be equally efficient in taking up rhodamine B. Ten minutes after injection in an antegrade perfusion, 95% of the dose was localized in the portal half of the acinus. Fifty minutes later, however, the amount of rhodamine B in Zone 1 had been reduced to 23%; 30 and 31% were in Zones 2 and 3, respectively, and the medium concentration was doubled. Thus, unchanged rhodamine B appeared to be transported downstream within the liver, either via the medium or directly from cell to cell, finally resulting in a relatively higher rhodamine B concentration in Zone 3. To obtain additional data, we designed a perfusion setup in which the zones could be studied separately. In both zones, the amount excreted into the medium was about 30 times the amount excreted into bile. Intracellular sequestration of rhodamine B and the rate constant for sinusoidal secretion were higher in Zone 3, while the sinusoidal uptake rates were equal; biliary excretion was higher in Zone 1. Acinar distribution changed with time because rhodamine B, primarily accumulated in Zone 1, was secreted into the sinusoids and taken up again by downstream cells. The finally higher rhodamine B concentration in Zone 3 was caused by a zonal heterogeneity in intracellular sequestration and sinusoidal secretion of rhodamine B.

Animals↗

PubMedDate not supplied

Heterogeneous acinar localization of the asialoglycoprotein internalization system in rat hepatocytes.

Desialylated glycoprotein is rapidly cleared from plasma by a receptor-mediated endocytic mechanism located on hepatocytes. We studied the hepatic acinar distribution of this asialoglycoprotein transport system with the ligand 125I-asialoorosomucoid using rat liver perfused in either antegrade or retrograde direction in combination with quantitative light microscopic autoradiography. Grain distribution along the acinus appeared dependent on the perfusion direction. A rather shallow zone 1 to zone 3 gradient was observed if livers were perfused in the normal direction. However, a statistically significantly steeper zone 3 to zone 1 gradient was detected in retrograde perfusions. Kinetic analysis of perfusate clearance profiles yielded a hepatic clearance of 21.6 +/- 1.3 ml per min in antegradely perfused liver. Hepatic extraction was calculated to be 60.1 +/- 7.4%. Biliary secretion of radioactivity amounted to 1.89 +/- 0.18% of the dose within 1 hr after injection and consisted of intact material (1.39 +/- 0.25%) and radioactive low-molecular-weight degradation products (0.52 +/- 0.08%), of which more than 90% could be accounted for by 125I-. Apart from a minor difference regarding biliary secretion of an unidentified glycopeptide (less than 0.1% of the injected dose), transport data for the retrogradely perfused livers were identical to those obtained with livers perfused in antegrade direction, emphasizing the functional equivalence of both groups of livers. The autoradiographic data indicate that zone 3 hepatocytes take up 125I-asialoorosomucoid more avidly than zone 1 cells. The kinetic and biochemical data indicate that further processing in the hepatocytes is virtually similar in the two zones.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

The applicability of rat and human liver slices to the study of mechanisms of hepatic drug uptake.

In the present study we investigated the applicability of the liver slice model to study mechanisms of drug uptake. Four model compounds were investigated that enter hepatocytes via entirely different membrane transport mechanisms. Rhodamine B (RB), which enters hepatocytes by passive diffusion, was homogeneously distributed throughout the rat liver slice (250 microm thickness) within 5 min, indicating that the penetration rate into the slice and the diffusion rate into the cells are rapid. In contrast, lucigenin (LU), which is taken up by hepatocytes through adsorptive endocytosis, was detected in the inner cell layers after 15 min. Digoxin uptake into the slice showed a temperature-dependent component and was stereoselectively inhibited by quinine, which is compatible with the involvement of a carrier-mediated uptake mechanism. The neo-glycoalbumin Lactose(27)-Human Serum Albumin (Lact(27)-HSA) and the negatively charged Succinylated-Human Serum Albumin (Suc-HSA) entered the slices and were taken up temperature-dependently into hepatocytes and endothelial cells, respectively. The liver slice preparation is a valuable tool to investigate the mechanisms of cellular uptake of drugs. Moreover, the precision-cut liver slices offer the unique possibility to study both hepatocyte and endothelial cell function in human and rat liver.

Aconitic Acid↗

PubMedDate not supplied

Potentials and limitations of the low-molecular-weight protein lysozyme as a carrier for renal drug targeting.

Selective targeting of drugs to the kidney may enable an increased renal effectiveness combined with a reduction of extrarenal toxicity. Intrarenal delivery to the proximal tubular cell can be achieved using low-molecular-weight proteins, such as lysozyme. Administration of high dosages of lysozyme, required to study the effects of such conjugates in vivo, however, is restricted since a partial escape of the renal reabsorption and the occurrence of unwanted effects on systemic blood pressure and renal function may occur. The purpose of this study was to investigate the optimal parenteral administration schedule and the maximum dose of lysozyme, providing the most optimal tubular reabsorption and at the same time a minimal effect on blood pressure and renal hemodynamics, comparing continuous infusion of lysozyme with single dose injections. Urinary lysozyme excretion increased dose-dependently, both during continuous infusion and intravenous bolus injections. However, this loss of intact lysozyme into the urine was much higher after 3 injections of in total 250 mg x kg(-1) x 6 h(-1) (51.8+/-3.7% of the dose) compared to the same dose administered by continuous infusion (11.7+/-2.4%, P < 0.001). Continuous infusion of lysozyme up to 1000 mg x kg(-1) in 6 hours had no effect on systemic blood pressure, whereas a bolus injection of lysozyme (167 mg x kg(-1)) resulted in reversible blood pressure lowering of 52.2+/-2.2% (P<0.001). A dose-dependent decline of the glomerular filtration rate was observed at dosages of lysozyme higher than 100 mg x kg(-1) x 6 h(-1), with a maximal reduction of 53.0+/-3.7% after infusion of 1000 mg x kg(-1) x 6 h(-1). Effective renal plasma flow was less affected and only lowered statistically significant at dosages of 500 (-12.6+/-3.3%, P<0.05) to 1000 mg x kg(-1) x 6 h(-1) (-17.2+/-3.9%, P<0.01). We conclude that bolus injections of lysozyme should not be used for renal targeting purposes since it results in considerable tubular loss of lysozyme in the urine as well as cardiovascular side effects. In contrast, continuous infusion of lysozyme using dosages sufficient for renal drug targeting (maximally 15 mg x kg(-1) x h(-1)) only has minimal effects on blood pressure and renal hemodynamics, with a minimal urinary lysozyme loss as well.

Animals↗

PubMedDate not supplied

Effect of nafenopin (SU-13,437) on liver functions. Hepatic uptake and biliary excretion of ouabain in the rat.

Pretreatment of rats for 2 days with the hypolipidemic drug, nafenopin, 0.5 g/kg, results in an increase in liver weight and bile flow. Despite these changes, hepatic transport of ouabain is reduced. This was demonstrated in the isolated perfused liver as well as in vivo. Although net uptake into liver is diminished in treated rats, the initial rapid phase of the plasma disappearance curve is unaffected. This suggests that the primary uptake process is unaffected by nafenopin or is altered in a manner that is not reflected in this phase of plasma disappearance. Alternatively, nafenopin may increase ouabain efflux from liver to plasma. Biliary excretion of ouabain is markedly suppressed after nafenopin pretreatment and higher liver levels of ouabain were encountered after the first 20 min in treated animals. The inference is drawn that liver to bile transport of ouabain is also suppressed by nafenopin pretreatment.

Animals↗

PubMedDate not supplied

The influence of dehydrocholate on hepatic uptake and biliary excretion of 3H-taurocholate and 3H-ouabain.

The hepatic uptake and biliary excretion of 3H-taurocholate and 3H-ouabain was studied in the rat during saline (control) and dehydrocholate infusions. Dehydrocholate (140 mumol/hr) did not influence the plasma disappearance nor the biliary excretion of taurocholate after a single iv injection (37 mumol/kg). Bile production in the dehydrocholate experiment was increased 2- to 3-fold compared with controls. The biliary transport maximum for exogenously administered taurocholate was determined by constant infusion to be 135.0 +/- 3.0 mumol/hr (22 mumol/min/g of liver). Concomitant infusions of 140 mumol of dehydrocholate per hr did not alter the maximal taurocholate output. The effects of the two bile salts on bile flow were additive. Dehydrocholate (140 mumol/hr) reduced the biliary excretion of 3H-ouabain (0.8 mumol/kg) and elevated the secondary slow component of the plasma disappearance of the cardiac glycoside. The hepatic levels of ouabain were increased compared with controls. It is concluded that dehydrocholate interferes with ouabain transport at the canalicular level but not with primary hepatic uptake. Taurocholate (140 mumol/hr) failed to influence the total biliary output of ouabain. These differences and the lack of interaction between dehydrocholate and taurocholate suggest a hepatic transporting pathway for taurocholate which differs from that for taurocholate which differs from that for dehydrocholate and/or its metabolites.

Animals↗