Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide.

1. The interference of resins and activated charcoal with the absorption of digoxin, carbamazepine and frusemide was studied. 2. In a cross-over study consisting of four phases, single doses of colestipol hydrochloride (10 g), cholestyramine (8 g), activated charcoal (8 g) or water only were given to six healthy volunteers immediately after the simultaneous ingestion of digoxin (0.25 mg), carbamazepine (400 mg) and frusemide (40 mg). Plasma and urine concentrations of the test drugs and the urine volumes were determined up to 72 h. 3. The absorption of digoxin was not reduced by colestipol, moderately (30-40%, P less than 0.05) reduced by cholestyramine and greatly (96%) by charcoal. 4. The absorption of carbamazepine was not decreased by cholestyramine, slightly (10%) by colestipol and greatly (90%) by activated charcoal. 5. The absorption and the diuretic effect of frusemide were significantly diminished by all agents. The bioavailability was reduced by colestipol 80%, by cholestyramine 95% and by activated charcoal 99.5%. 6. The interference with the gastrointestinal absorption of most of the basic drugs by colestipol and cholestyramine seems to be minimal. On the other hand, the resins may seriously impair the absorption of certain acidic drugs, for example frusemide.     

Sorbent therapy of the porphyrias. IV. Adsorption of porphyrins by sorbents in vitro

The adsorption capacities (Qm's) of the ion exchange resin cholestyramine and 8 activated charcoals for uroporphyrin, protoporphyrin and coproporphyrin, porphyrins that accumulate within tissues or vasculature in certain porphyrias, have been determined. Qm's (mg porphyrin/gm dry sorbent) were derived from Langmuir isotherms, which were constructed from experiments that assessed the amount of porphyrin adsorbed after the addition of varying amounts of porphyrin in solution to a constant amount of sorbent. These experiments were carried out at pH 8.2 in 0.5% desoxycholate, to simulate conditions of the small intestine. For uroporphyrin I, the Qm for Amoco Supersorb PX-21 highly activated charcoal was greater than that for cholestyramine (mean +/- SD of 26.5 +/- 12.7 vs. 17.0 +/- 2.6; t'32 = 2.46, P less than 0.025) and highly significantly greater than those of the other charcoals. For protoporphyrin IX, cholestyramine and Amoco Supersorb PX-21 charcoal had the highest Qm's (32.4 +/- 8.6 and 30.9 +/- 9.2), but these were not significantly greater than the Qm's of 5 other charcoals. Little difference was found among sorbents in the rate of adsorption of either porphyrin. For coproporphyrin III, the Qm's of cholestyramine and Amoco Supersorb PX-21 charcoal were not significantly different (39.2 +/- 13.7 vs. 35.1 +/- 4.0) but they were greater than that of Norit USP XX (20.0). Virtually no desorption of porphyrin from either cholestyramine or Amoco Supersorb PX-21 charcoal was detected. Both cholestyramine and Amoco Supersorb PX-21 charcoal appear to be highly avid sorbents for porphyrins of varied states of carboxylation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a salt of cholestyramine and 2-[4-(p-chlorobenzoyl)phenoxy]2-methyl propionic acid (alpha-1081) on biliary lipid secretion in rats

1 Hypolipidaemic agents may increase biliary cholesterol in man, inducing a supersaturated bile. 2 To evaluate this possible side-effect, we have studied bile lipid secretion over a period of 8 h with intact enterohepatic circulation and 4 h with complete interruption in rats treated for two months with a salt of cholestyramine and 2-[4-(p-chlorobenzoyl)-phenoxy]2-methyl propionic acid (alpha-1081, 1.150 g/kg body wt., daily), cholestyramine (1.125 g/kg body wt. daily), procetofenic acid (25 mg/kg body wt. daily) and saline respectively (six rats for each group). 3 Cholesterol saturation index significantly (P less than 0.005) increased (from 0.21 +/- 0.01 to 0.39 +/- 0.09, mean +/- s.d.), in rats fed with procetofenic acid but it did not in alpha-1081- and cholestyramine-treated animals. 4 Procetofenic acid and, to a lesser extent, cholestyramine increased the bile flow. Procetofenic acid increased cholesterol secretion from 0.45 +/- 0.17 to 0.94 +/- 0.19 mumol kg-1 body wt. h-1 (mean +/- s.d.). 5 Cholestyramine increased both serum cholesterol and bile acid secretion from 0.45 +/- 0.17 to 0.68 +/- 0.10 and 25.8 +/- 9.48 to 39.96 +/- 6.68 mumol kg-1 body wt. h-1 respectively; alpha-1081, on the contrary, had no effect on bile lipid secretion. 6 These data suggest that alpha-1081 may be used as a new hypolipidaemic drug without any risk of increasing cholesterol in bile.     

Effect of resin surface charge on gastric mucoadhesion and residence of cholestyramine

Previous studies performed on excised gastric tissue and in healthy volunteers revealed that the ion exchange resin, cholestyramine, exhibits mucoadherent behaviour. This study was designed to elucidate whether surface charge affected this behaviour. Gamma scintigraphy was performed on fasted normal subjects following oral administration of cholestyramine or the cationic exchanger Amberlite(R) IRP-69, either uncoated or polymer-coated to mask their charge. Subjects were fed after 4 h. The initial gastric emptying of all formulations was similar (T(50) values (mean+/-S.E.M.): cholestyramine=85.86+/-9.16 min; IRP-69=76.09+/-9.23 min; polymer-coated cholestyramine=72.0+/-12.64 min; polymer-coated IRP-69=70.25+/-10.57 min: P=0.724). However, after 3 h the emptying pattern of cholestyramine was slower than that of IRP-69. This resulted in greater retention times than IRP-69 (AUC(0-6) values (relative units)=15,200+/-1093 versus 9452+/-811; cholestyramine versus IRP-69: P=0.0004). This effect was reduced by polymer-coating the cholestyramine. Serial images showed that cholestyramine was trapped in the oropharyngeal region and subsequently displaced by the meal, resulting in higher levels of activity remaining at 6 h. Thus, cholestyramine exhibited prolonged gastric residence via mucoadhesion and was distributed throughout the stomach. The surface charge of the resin was found to have a contributory role. These materials may have potential for the delivery of drugs in the topical treatment of the gastric mucosa, for example in the eradication of Helicobacter pylori.     

The effect of colestipol and cholestyramine on the systemic clearance of intravenous ibuprofen in rabbits

Abstract— The effect of oral administration of the non-absorbable anion-exchange resins cholestyramine and colestipol on the systemic clearance and other pharmacokinetic parameters of intravenously administered ibuprofen (25 mg kg^?1) was studied in rabbits. Single doses of colestipol hydrochloride (0·4 g kg^?1) or cholestyramine (0·17 g kg^?1) were given 30 min before ibuprofen administration. In cholestyramine-treated rabbits a significant reduction in ibuprofen plasma concentration was observed compared with both control (water only) and colestipol-treated rabbits. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half-life and the mean residence time. Furthermore, a 31% increase in the systemic clearance and 23% decrease in the area under the plasma concentration-time curve were also observed in cholestyramine-treated rabbits. Colestipol treatment did not change these parameters. The volume of distribution parameters (Vd_ss and Vd_area) did not change following either treatment. The changes in the pharmacokinetic parameters are compatible with an acceleration of ibuprofen elimination induced by oral administration of cholestyramine and not by colestipol. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.     

Acceptability of cholestyramine or colestipol combinations with six vehicles

Preferences for cholestyramine or colestipol in combination with orange drink, orange juice, grape juice, apple juice, water, or apple sauce were evaluated in 40 healthy adults. Each subject evaluated the taste, texture, and smell of 30-mL samples of 12 drug-vehicle combinations (two drugs, six vehicles) using modified five-point wine-tasting scales. Samples were prepared to contain either cholestyramine 1.0 g or colestipol hydrochloride 1.3 g. The products were tested at room temperature and were administered in a random order. Subjects and observers were blinded to the identity of the products. Acceptability scores for taste, texture, and smell were significantly higher for cholestyramine than for colestipol. Total mean preference scores for cholestyramine-vehicle combinations ranged from 9.9 to 11.7; for colestipol, 6.3 to 8.9. Orange drink, apple juice, grape juice, and orange juice were the preferred vehicles for cholestyramine. The preferred vehicles for colestipol were orange drink, apple sauce, and apple juice.     

Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide

Background: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide’ s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6–8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations – such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies.

Methods: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days.

Results and conclusions: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.     

Opioid receptor blockade promotes weight loss and improves the display of sexual behaviors in obese Zucker female rats.

Obese Zucker female rats are hyperphagic, overweight, infertile, and hyporesponsive to the inductive effects of ovarian steroid hormones on sexual behaviors. It has been postulated that endogenous opioid activity may contribute to their obesity and reproductive dysfunction. To test this hypothesis, ovariectomized, adult obese Zucker rats were treated with the opioid receptor antagonist, naltrexone, or saline prior to measurement of steroid-induced sexual behaviors, food intake, and body weight. In estradiol benzoate (EB)-treated rats, naltrexone injection increased the display of sexual receptivity (lordosis quotient, LQ: saline, 11+/-10%; 5 mg/kg naltrexone, 54+/-15%, p < 0.05) and also elicited proceptivity (PRO), which was never observed after saline injection. In EB plus progesterone-treated animals, naltrexone administration enhanced both sexual receptivity and proceptivity (LQ: saline, 17+/-10%; 5 mg/kg naltrexone, 96+/-3%; p < 0.05; PRO: saline, 3.0+/-2.4 bouts/min; 5 mg/kg naltrexone, 45.3+/-12 bouts/min; p < 0.01). Naltrexone injection also decreased 24-h food intake (saline, 24.2+/-0.7 g; 5 mg/kg naltrexone, 17.6+/-1.2 g; p < 0.05) and weight change (saline, +7.3+/-0.8 g; 5 mg/kg naltrexone, -4.5+/-1.4 g, p < 0.01). Morphine treatment blocked these effects of naltrexone on sexual behaviors, food intake, and body weight. These data suggest that endogenous opioids contribute to hyperphagia, obesity, and behavioral hyporesponsiveness to ovarian steroid hormones in obese Zucker rats.     

Effect of colestipol,a new bile acid sequestrant,on the absorption of phenprocoumon in man

Summary The effect of colestipol, a basic anion-exchange resin, which lowers the serum cholesterol level, has been examined on the absorption of phenprocoumon in four human volunteers,in vivo. Plasma concentrations of phenprocoumon were determined after the simultaneous ingestion either of 8 g colestipol or 4 g placebo (microcrystalline cellulose) and 12 mg phenprocoumon according to a randomized crossover repetition design. The plasma levels were not affected by colestipol, suggesting that it had no effect on the absorption of phenprocoumon. —In vitro, the phenprocoumon-binding capacity of colestipol was the same as that of cholestyramine, except in buffers at pH 5 when there was a marked decrease in the colestipol binding.     

Effects of cholestyramine and colestipol on the plasma concentrations of propranolol

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4'-hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4'-hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4'-hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen.     

Pharmacokinetic evaluation of (-)-6-aminocarbovir as a prodrug for (-)-carbovir in rats.

The recently synthesized carbocyclic 2',3'-didehydro-2',3'-dideoxy-6-deoxy-6-amino-guanosine [(-)6AC] was evaluated as a prodrug for carbovir, carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine [(-)CBV] in seven male Sprague-Dawley rats. A randomized three-way cross-over design was used. Rats were assigned to receive the following treatments: a 20 mg/kg (-)6AC infusion, 40 mg/kg (-)6AC orally, and a 20 mg/kg (-)CBV infusion. Blood samples were collected over 480 min, and urine was collected for up to 48 hr. A 2- to 3-day washout period was observed between treatments. Following i.v. infusion, (-)6AC concentrations in the blood declined rapidly in a monoexponential pattern with an elimination half-life of 11.3 +/- 3.3 min (mean +/- SD, n = 7). The time-averaged total body clearance was 115.7 +/- 32.6 ml/min/kg. The fraction of the dose excreted unchanged in urine was 0.28 +/- 0.06. The fraction of the (-)6AC dose metabolized to (-)CBV was 0.48 +/- 0.14. Following oral administration of (-)6AC, the bioavailability of (-)CBV was 46.2 +/- 9.9% (n = 6) in comparison with the bioavailability of approximately 20% previously obtained after an oral dose of (-)CBV. The Cmax of (-)CBV after a 40 mg/kg oral dose of (-)6AC was 1.65 +/- 0.7 micrograms/ml as compared with the previously reported Cmax of 1.00 microgram/ml obtained after a 60 mg/kg oral dose of (-)CBV. (-)6AC has considerable potential for the improvement of the extent of absorption of (-)CBV from oral dosing.     

Polymeric sorbents for bile acids. I: Comparison between cholestyramine and colestipol.

Isotherms for the sorption of bile acids at 20 degrees C, in tris(hydroxymethyl)aminomethane.HCl(tris) and KH2PO4-NaOH (phosphate) buffers (pH 7.4), indicate that the binding by cholestyramine and colestipol is mainly through ionic linkages, although hydrophobic interactions are also of importance. Cholestyramine has a higher sorption capacity for bile acids, in both buffers, than colestipol. The chloride form of cholestyramine has a higher capacity for cholate in tris buffer than the iodide form. Increased ionic strength of the medium leads to decreased amounts of sorption.     

The effect of colestipol and cholestyramine on ibuprofen bioavailability in man

The purpose of this study was to determine whether a concomitant single oral dose of one of the anion exchange resins colestipol hydrochloride (10 g) or cholestyramine (8 g) administered with ibuprofen (400 mg) would alter the bioavailability of this non-steroidal anti-inflammatory agent. The study was performed according to a randomized three-way crossover design in six healthy male volunteers. After dosing, serial blood samples were collected for a period of 10 h. Plasma harvested from blood was analysed for ibuprofen by a sensitive high-performance liquid chromatographic method. There were no significant differences between colestipol treatment and control for peak plasma concentration (C_max), time to peak concentration (T_max), area under the plasma concentration—time curve (AUC), mean residence time (MRT), elimination rate constant (K_el), or elimination half-life (t_1/2). Cholestyramine treatment resulted in a significant decrease in AUC (26%, p< 0.05) and C_max (34.4%, p <0.01) and a significant increase in T_max (80%, p < 0.01) and MRT (20.2%, p < 0.05). Cholestyramine administration showed no significant effect on the K_el and t_1/2 values. A significant correlation was obtained between the increase in MRT and the increase in T_max. The confidence intervals (90%) of the mean values of the pharmacokinetic parameters (AUC_O–∞ and C_max) for the colestipol : control ratio were well within the acceptable range of 100 ± 20, whereas those for the cholestyramine : control ratio were outside it. Colestipol treatment was found to be bioequivalent to the control treatment by Schuirmann's two one-sided t tests, while cholestyramine treatment was found to be bioinequivalent. The results indicate a lack of interaction between ibuprofen and colestipol and a potential significant interaction (decrease in rate and extent of absorption of ibuprofen) between cholestyramine and ibuprofen in patients receiving concurrent therapy.     

Effects of rice bran fibre and cholestyramine on the faecal excretion of Kanechlor 600 (PCB) in rats

1. As rice bran fibre binds Kanechlor 600 (PCB), the present study was conducted to determine whether the fibre stimulates rat faecal excretion of PCB in vivo. 2. In rats fed diets containing rice bran fibre, lignin and cholestyramine, the faecal excretion of PCB was increased. Total PCB excreted in rat faeces for groups fed diets of 10% (w/w) rice bran fibre, 10% fibre plus 5% lignin, 5% cholestyramine and 10% fibre plus 5% cholestyramine were 3.4, 3.7, 2.2 and 5.4 times as much, respectively, as that of control rats. The greatest effect on the faecal excretion of PCB was thus obtained with rice bran fibre plus cholestyramine. 3. In rats fed these diets, PCB concentration of the small intestine was significantly decreased to 25-50% of that of controls. PCB of spleen in rats fed diets of 10% fibre, 10% fibre plus 5% lignin and 10% fibre plus 5% cholestyramine also decreased to 50% of that of controls. However, PCB of other tissues were not affected.     

Some studies on the rodenticidal action of indomethacin.

The oral LD50 of indomethacin for a seven-day observation was found to be 12.58 +/- 1.15 mg/kg. At LD10 of 6.61 mg/kg, a dose to weight ratio of 28 was obtained for a 240 g rat, while at a maximum single dose of 3 mg/kg in man it is only 0.04. Neither diazepam nor phenobarbital influenced death at the doses of both drugs used. However, cholestyramine 2 g/kg/day was found to protect by 50% from the LD100 of indomethacin. Gross pathological studies showed dose-dependent ulceration and perforation (P < 0.001, 12 vs 24 mg/kg) and such lesions occurred in starved rats, were low in bile duct-ligated compared to sham-operated rats (P < 0.001) and were also low in cholestyramine-treated rats. Indomethacin-induced lethality in rats was found to be dose-dependent.     

Correlative studies of the hypocholesterolemic effect of a highly activated charcoal

We have carried out in vitro and animal studies to determine the cholesterol lowering efficacy of activated charcoals vs. cholestyramine. In the in vitro studies, we determined the adsorption capacity (Qm) of cholestyramine and activated charcoals for cholesterol in glacial acetic acid. Mean (+/- SD) Qm's (mg cholesterol adsorbed/gm dry sorbent) decreased in the order Super Char highly activated charcoal (277 +/- 121), Norit USP XX charcoal (33 +/- 10), Acta-Char charcoal (26 +/- 4), Mallinckrodt USP charcoal (26 +/- 10), Norit A charcoal (22 +/- 4) and cholestyramine (0). For the bile salt sodium desoxycholate in ammonia: sodium bicarbonate, pH 8.2, the Qm with cholestyramine was 4641 +/- 2669 and with Super Char was 2814 +/- 667 (p = 0.11). We then contrasted the effect of cholestyramine (1%, added to the diet) and Super Char (1% or 2%) on plasma cholesterol concentrations in rabbits made hypercholesterolemic with a diet containing casein. The percent reductions were 61 in one rabbit fed cholestyramine, 61 and 67 in two rabbits fed 1% Super Char, and 90 in one rabbit fed 2% Super Char. In WHHL homozygous rabbits, reductions in plasma cholesterol from pre-treatment and post-treatment levels, respectively, averaged 52% and 38% with 2% cholestyramine (2 animals), 70% and 43% with 2% Super Char (2 animals), and 70% and 63% with 4% Super Char (3 animals). The effectiveness of cholestyramine in animals that lack functional cellular receptors for low density lipoprotein was unexpected. Super Char charcoal appears to be an effective hypocholesterolemic agent, warranting study in man.     

Apparent reduced absorption of gemfibrozil when given with colestipol

Colestipol and gemfibrozil may be used in combination to lower serum cholesterol and triglycerides. Since colestipol is known to bind certain anionic drugs, we studied the effect of colestipol on the pharmacokinetics of gemfibrozil in 10 patients with elevated serum cholesterol and triglycerides. Each patient received 600 mg of gemfibrozil by mouth during four different studies. Gemfibrozil was given randomly either alone, with, 2 hours before, or 2 hours after 5 grams of colestipol. The serum gemfibrozil concentration time curves were similar when gemfibrozil was given alone or two hours before or after colestipol. There was also no statistical difference in peak gemfibrozil concentration (Cmax), time to Cmax (tmax), area under the curve (AUC), or serum elimination half-life (t1/2) between any of these three treatments. However, when colestipol was given with gemfibrozil, there was a decrease in AUC (43.6 +/- 21.9 mg*hr/L) compared with gemfibrozil given alone (62.6 +/- 10.3 mg*hr/L) which was statistically different by both ANOVA and paired t-test. This finding suggests a decrease in gemfibrozil bioavailability. Cmax when colestipol was given with gemfibrozil (14.7 +/- 6.6 mg/L) was not statistically different from gemfibrozil alone (20.1 +/- 4.9 mg/L). However, the mean serum concentrations when gemfibrozil was given with colestipol were significantly lower at the 0.5, 1.0 and 1.5 hour sampling times when compared to the other regimens. Gemfibrozil serum elimination half-life was not significantly altered by combination with colestipol. The data suggest a reduction of gemfibrozil bioavailability when colestipol is administered concomitantly. Separating the administration of these two drugs by at least two hours will avoid this drug interaction.     

Pravastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia.

Pravastatin is an HMG-CoA reductase inhibitor which reduces plasma cholesterol levels by inhibiting de novo cholesterol synthesis and increasing the receptor-mediated catabolism of low density lipoprotein (LDL). Several large multicentre placebo-controlled trials have shown that pravastatin reduces total and LDL-cholesterol levels in a dose-proportional manner in patients with familial or nonfamilial hypercholesterolaemia. Reductions in LDL-cholesterol levels reported in the largest study were 18% (10 mg/day), 23% (20 mg/day) and 31% (40 mg/day) after 12 weeks. Once-daily administration appears to be as effective as two daily doses. Pravastatin consistently increases HDL-cholesterol levels and decreases levels of total triglycerides but these changes are not dose dependent. At the study dosages used, the antihypercholesterolaemic effects of pravastatin were superior to those of bezafibrate and clinofibrate, and were similar to those of simvastatin, lovastatin, gemfibrozil and cholestyramine although in some studies a trend towards a superior effect with pravastatin was seen. Pravastatin did not reduce HDL-cholesterol like probucol, or increase triglyceride levels like cholestyramine. Combined treatment with pravastatin and cholestyramine or colestipol enhances the cholesterol-lowering effects of either drug administered alone and offsets the increase in total triglyceride levels seen with cholestyramine or colestipol therapy. Pravastatin is well tolerated during treatment of up to 24 months but longer term tolerability has not yet been established. The effect of provastatin on cardiovascular events related to elevated plasma cholesterol levels is under investation in several large scale regression and primary and secondary prevention trials.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey. 2. After a single oral dosing of 14C-I (10 mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 +/- 0.3% in rat, 46.9 +/- 1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey. 3. After a single i.v. dose of 14C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71 +/- 0.01 to 0.93 +/- 0.05 as the dose was increased from 0.2 to 20 mg/kg.     

Studies on auromomycin.

A new antitumor antibiotic, named auromomycin, was isolated from the culture broth of Streptomyces macromomyceticus, a macromomycin-producing strain. The antibiotic was recovered from the culture filtrate by salting out with ammonium sulfate and further purified by successive application of ion-exchange chromatography on Amberlite IRA-93 (Cl form) and DEAE-Sephadex (OH form), Gel filtration on Sephadex G-50 and hydrophobic chromatography on Octyl-Sepharose CL-4B. The antibiotic is an acidic polypeptide with a molecular weitht of 12,500 and an isoelectric point of pH 5.4 and consists of 16 different amino acids. It has characteristic absorption maxima at 273 nm and 357 nm in the ultraviolet spectrum and two minima at 280 nm and 350 nm in the optical rotatory dispersion spectrum. Auromomycin exhibits antibacterial activity not only against Gram-positive bacteria, but also Gram-negative bacteria. Antitumor activities of auromomycin were revealed against EHRLICH ascites carcinoma, ascites sarcoma 180, L1210 leukemia and LEWIS lung carcinoma. Auromomycin was found to be converted into macromomycin by adsorption chromatography on Amberlite XAD.