Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo.

Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05 +/- 0.2 to 2.41 +/- 0.43 ml min-1 kg-1 (P < 0.001) and the colchicine bile/plasma ratio from 146 +/- 8 to 35 +/- 5 (P < 0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5 +/- 3 vs post-SDZ PSC-833: 2.48 +/- 0.94 ml min-1 kg-1; P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228 +/- 64 vs post-SDZ PSC-833: 48 +/- 22; P < 0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multi-drug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.

Effect of cyclosporine on colchicine partitioning in the rat liver.

Colchicine is secreted into bile as a major pathway of elimination. Cyclosporine (CsA) inhibits colchicine biliary secretion. In the present study, the effects of cyclosporine and its vehicle (cremophor) on the partitioning of colchicine across the liver were studied. CsA decreased the colchicine bile/plasma ratio from 484 +/- 39 to 53 +/- 3 (P < 0.001). This effect was due to both a decrease in bile/liver partitioning (control, 35.1 +/- 1.2, vs CsA treatment, 9.2 +/- 0.5; p < 0.001) as well as a decrease in liver/plasma partitioning (control, 13.7 +/- 0.8, vs CsA treatment, 5.7 +/- 0.4; P < 0.001). Cremophor also decreased the colchicine bile/plasma ratio (317 +/- 19, P < 0.02 vs control), but this effect was due to a decrease in the liver/plasma ratio (9.99 +/- 0.7, P < 0.02 vs control) rather than the bile/liver ratio (31.9 +/- 2.1, P > 0.2 vs control). Inhibition at the canalicular membrane is consistent with the location of gp-170, the presumed transporter of colchicine.

Effect of cyclosporine on colchicine secretion by a liver canalicular transporter studied in vivo.

The multidrug resistance transport protein is a normal constituent of the liver canalicular membrane, although its function has not been defined in vivo. Colchicine, a multidrug resistance substrate, is eliminated mainly by the liver. Cyclosporine reverses multidrug resistance in vitro, presumably by inhibiting the multidrug resistance transporter. This study assesses biliary colchicine elimination and the effect of cyclosporine on this process. After cyclosporine administration biliary colchicine clearance decreased from 11.6 +/- 0.8 to 2.2 +/- 0.4 ml/min.kg (p less than 0.05), and the colchicine bile/plasma ratio decreased from 166 +/- 9 to 38 +/- 5 (p less than 0.05). Cremophor EL (a cyclosporine vehicle) transiently inhibited biliary colchicine clearance and colchicine bile/plasma ratio, but to a much smaller extent than cyclosporine in vehicle. Biliary cyclosporine clearance was 0.122 and 0.024 ml/min.kg after bolus doses of 2 or 10 mg/kg intravenously, respectively. Cyclosporine bile/plasma ratio was 1.3 to 5.2. When cyclosporine was given 16 hr before colchicine infusion, biliary colchicine clearance decreased 39% (p less than 0.05), and colchicine bile/plasma ratio decreased 51% (p less than 0.05). Thus colchicine is actively secreted into bile and will be useful in the study of the multidrug transporter in vivo. Cyclosporine profoundly inhibits colchicine secretion into bile but is itself mainly metabolized rather than secreted. If competition for a common carrier is the basis for the interaction, then cyclosporine represents a drug that binds to but is not transported by the canalicular transporter.

Effect of cyclosporine on colchicine secretion by the kidney multidrug transporter studied in vivo.

The multidrug resistance (MDR) transport protein is a normal constituent of proximal renal tubules although its function has not been defined in vivo. We find that colchicine, an MDR substrate, is secreted into urine by a process which is distinct from the organic cation transporter responsible for tetraethylammonium and N-methylnicotinamide secretion. Cyclosporine (CsA), which reverses MDR in vitro presumably by inhibiting the MDR transporter, inhibits colchicine renal secretion but does not inhibit the net secretion of the organic cation, ranitidine, or the organic anion, p-aminohippurate. After CsA (2 mg/kg i.v.), colchicine renal clearance decreased from 6.23 +/- 0.46 to 3.58 +/- 0.31 ml/min.kg (P less than .05), glomerular filtration rate was unchanged (4.21 +/- 0.08 and 3.88 +/- 0.17 ml/min.kg, before and after CsA, respectively; P = .09) and colchicine secretory ratio decreased from 1.48 +/- 0.11 to 0.92 +/- 0.07 (P less than .05). Cremophor (CsA vehicle) increased colchicine renal clearance (6.77 +/- 0.29 to 7.7 +/- 0.3 ml/min.kg, P less than .05) and colchicine secretory ratio (1.425 +/- 0.071 to 1.621 +/- 0.061, P less than .05). The inhibition of colchicine secretion was long-lived lasting at least 30 hr after CsA. Thus, colchicine is actively secreted into urine by the multidrug transporter in vivo. CsA profoundly inhibits colchicine secretion into urine while having no effect on the secretion of the organic cation ranitidine or the organic anion p-aminohippurate.

Colchicine clearance is impaired in alcoholic cirrhosis.

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.

The effect of liver dysfunction on colchicine pharmacokinetics in the rat.

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), alpha-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min.kg +/- 8.27 ml/min.kg, a half-life of 16.68 min +/- 0.97 min and a volume of distribution of 1.84 L/kg +/- 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p less than 0.05) and half-life to increase by 38% (p less than 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p less than 0.05), terminal half-life increased to 513.7 min +/- 106.6 min (p less than 0.05) and volume of distribution increased by 175% (p less than 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxic delirium in a patient taking amantadine and trimethoprim-sulfamethoxazole.

Acute mental confusion occurred in a patient on a stable dose of amantadine after he was started on trimethoprim-sulfamethoxazole. Discontinuation of the drugs led to rapid improvement. Studies in a rat model of organic cation secretion demonstrate that both amantadine and trimethoprim, but not sulfamethoxazole, inhibit the renal secretion of the organic cation procainamide. This case may represent an amantadine-trimethoprim interaction.

[Importance of the function of polymorphonuclear neutrophils in intrinsic and extrinsic asthma. Interaction of whole serum in the control of cellular activity]. / Importancia de la función de los polimorfonucleares neutrófilos en el asma intrínseco y extrínseco. Interacción del suero total en el control de la actividad celular.

A study was made of polynuclear leucocyte function: chemotaxis, NBT reduction and the influence of total plasma on chemotaxis, was investigated in a large group of asthmatic paediatric patients, both during and between asthmatic attacks. It has been proved that polynuclear function is different in the two types of asthma. During the asthmatic's crisis and in the intrinsic patients in intercrisis periods, there is a polynuclear neutrophil hyperreaction when the chemotaxis and the NBT reduction are raised. An inhibited chemotactic activity in the plasma of these patients is noted. This activity doesn't produce irreversible effects on the cells; it acts as a regulating mechanism on the chemotactic factors found in plasmatic fractions.

Additive protection of cimetidine and N-acetylcysteine treatment against acetaminophen-induced hepatic necrosis in the rat.

Cimetidine protects against acetaminophen hepatotoxicity in the rat as evidenced by improved survival, lower serum aminotransferases, improved liver histology, decreased in vivo and in vitro covalent binding of acetaminophen to liver protein and decreased rate of glutathione depletion. This protection is best explained by inhibition of acetaminophen oxidation by cimetidine. N-acetylcysteine, the accepted antidote, protects against acetaminophen hepatotoxicity primarily by enhancing glutathione synthesis. Inhibition of acetaminophen oxidation by cimetidine has been demonstrated directly in vitro with both rat and human liver microsomes. The aim of the present study was to determine whether cimetidine and N-acetylcysteine might be additive in their protection against acetaminophen hepatotoxicity as cimetidine and N-acetylcysteine have different mechanisms of protective action. Treatment with either cimetidine or N-acetylcysteine improved survival and serum transaminases in a dose-related manner but protection by the combination was additive when compared to each agent alone. Cimetidine decreased the rate of hepatic glutathione depletion and acetaminophen covalent binding in vivo in a dose-dependent manner whereas only a high dose of N-acetylcysteine decreased covalent binding. However, the combination of cimetidine and N-acetylcysteine more effectively prevented glutathione depletion and covalent binding in vivo than either agent used alone. We conclude that protection against acetaminophen hepatotoxicity using a combination of cimetidine and N-acetylcysteine is better than that found with either agent alone. Inasmuch as cimetidine does not increase hepatic glutathione per se, or does N-acetylcysteine inhibit acetaminophen oxidation, the additive protection against acetaminophen hepatotoxicity is best explained by the above mentioned mechanisms of action for each agent.

Effect of ketoconazole on hepatic oxidative drug metabolism.

Several clinical reports have suggested (but not demonstrated) that ketoconazole, a broad-spectrum antifungal drug, may inhibit hepatic oxidative drug metabolism in man. We recently demonstrated that ketoconazole inhibits caffeine and aminopyrine oxidation in the rat; we now study the influence of ketoconazole on theophylline and chlordiazepoxide kinetics in man. These studies were performed before and after varying doses of ketoconazole within the currently accepted therapeutic range. Ketoconazole had no effect on theophylline clearance, whereas the drug impaired chlordiazepoxide clearance from plasma. After a single dose of ketoconazole, there was a 20% decrease in clearance and a 26% decrease in volume of distribution without evidence of inhibition of drug metabolism. These changes apparently were not related to ketoconazole dose. After repetitive dosing with ketoconazole, chlordiazepoxide clearance decreased by 38% and was associated with reduced concentrations of its first oxidative metabolite, N-desmethylchlordiazepoxide. We conclude that ketoconazole inhibits at least one subset of the hepatic mixed-function oxidase system, but is not as general an inhibitor of hepatic oxidative drug metabolism as cimetidine appears to be. For some coadministered drugs, ketoconazole may also have an effect on other kinetic parameters such as volume of distribution. Therefore, we caution that clinically important drug interactions may occur with the concurrent use of ketoconazole.

The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro.

Ketoconazole is a new antifungal drug which has increasing clinical application due to its wide spectrum of activity and oral availability. Since substituted imidazoles may be potent inhibitors of cytochrome-mediated drug oxidation, we have examined the effect of ketoconazole on aminopyrine and caffeine metabolism in the rat. The 14C breath test was used to determine the elimination rate of aminopyrine and caffeine in vivo after single and chronic (7 day) treatment with ketoconazole. Acutely, ketoconazole (50 mg/kg) impaired markedly both aminopyrine (56% inhibition) and caffeine demethylation (83% inhibition). Inhibition of aminopyrine and caffeine demethylation as studied with the breath tests was related to ketoconazole dose. The decreased rate of aminopyrine demethylation measured by breath test correlated with decreased aminopyrine clearance from plasma after iv dosage. Chronic treatment with ketoconazole further increased the inhibition of aminopyrine demethylation while chronic treatment was associated with less inhibition of caffeine demethylation than found with a single dose. Breath tests repeated up to 72 hr after ketoconazole treatment revealed differences in aminopyrine and caffeine demethylation. At 24 hr after ketoconazole, aminopyrine demethylation was still inhibited at 78% of controls whereas caffeine demethylation was enhanced to 146% of control. Binding of ketoconazole to microsomal P-450 was determined by spectral analysis. A type II difference spectrum was found with absorbance maximum at 430 nm and minimum at 390 nm. Scatchard analysis revealed a biphasic interaction with estimated dissociation constants of 0.6 and 3.69 microM. Aminopyrine N-demethylation in vitro was markedly impaired with an I50 for ketoconazole of 27 microM and Ki of 8.5 microM.(ABSTRACT TRUNCATED AT 250 WORDS)