Improvement of the absorption of oral (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, an anti-varicella-zoster virus drug, in rats and monkeys.

In an effort to improve the gastrointestinal absorption of (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [(+/-)2HM-HBG], various salts and esters of the compound were synthesized and pharmacokinetic experiments were performed in rats and monkeys. The sodium or hydrochloride salts and short-chain esters of (+/-)2HM-HBG showed bioavailability characteristics that were equally as poor as those of (+/-)2HM-HBG. However, the esters given as salts tended to be better absorbed than the parent compound. The 6-deoxy and 6-deoxydiacetate analogs were extensively oxidized in vivo and represent prodrugs with considerable potential in improving the absorption of oral (+/-)2HM-HBG.

Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug.

The acyclic guanosine analog (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, (+/-)2HM-HBG, is an effective inhibitor of herpes simplex virus and varicella-zoster virus infections in vitro. This report is concerned with the pharmacokinetic evaluation of the drug in rats and monkeys and its antiviral activity in African green monkeys infected with simian varicella virus (SVV), a virus closely related to varicella-zoster virus that is also susceptible to inhibition by (+/-)2HM-HBG. Elimination half-lives in plasma following intravenous administration to monkeys (100 mumol/kg of body weight) ranged from 1.8 to 2.2 h, and total body clearance was 9.0 +/- 0.4 ml/min per kg (mean +/- standard error). After oral administration, levels in plasma were low, with a maximum concentration of the drug of only 3.1 +/- 0.8 microM, a time to reach maximum concentration of drug of 2.7 +/- 0.4 h, and an oral bioavailability of 10.6 +/- 1.4%. Because of the low oral bioavailability, SVV-infected monkeys were treated intramuscularly with (+/-)2HM-HBG. (+/-)2HM-HBG at a dosage of 10 mg/kg of body weight per day allowed moderate viremia, whereas a dosage of 30 mg/kg of body weight per day strongly suppressed viremia with minimal numbers of virus plaques from blood specimens collected at days 3, 5, and 7 postinfection and complete clearance at day 9 postinfection. Titers of antibody to SVV were also low. Treatment three times daily was somewhat more efficacious than treatment twice daily. Thus, (+/-)2HM-HBG is an effective inhibitor of SVV replication in vivo, despite the fact that leves of (+/-)2HM-HBG in plasma were low at extended periods of time and below the concentration of drug giving 50% inhibition of plaque formation obtained in vitro.

Effects of the dopamine D2 selective receptor antagonist remoxipride on dopamine turnover in the rat brain after acute and repeated administration.

The effects of the dopamine D2 selective receptor antagonist, remoxipride, on dopamine turnover in the rat brain were studied after acute and repeated administration and compared with the effects of haloperidol. Acute administration of remoxipride produced a dose-dependent increase of the concentrations of DOPAC and HVA in both striatum and olfactory tubercle + nucleus accumbens. The maximal effect of both acute remoxipride and haloperidol on dopamine turnover was attained approximately 2 hours after a single intraperitoneal administration, whereas a biphasic response was seen after oral remoxipride. Tolerance to the effects of repeated haloperidol (20 mumol/kg orally) treatment on dopamine turnover was observed as soon as after 3 days, whereas no such tolerance could be found during the first 15 days of repeated treatment with remoxipride (20 mumol/kg orally). A dose-related tolerance to the effects of remoxipride was, however, seen at higher dosages (40, 150 and 600 mumol/kg orally) and after a longer period (6 months) of treatment.

Elimination pattern and tissue distribution of intravenous iron-poly (sorbitol-gluconic acid) complex in the rat.

The elimination pattern and tissue distribution in rats of intravenous [14C-gluconic acid]-poly(sorbitol-gluconic acid) and 59Fe-iron-poly(sorbitol-gluconic acid) complex, glusoferron (Ferastral) have been examined. Twenty-four hours after injection of 20 or 200 mg/kg of [14C-gluconic acid]-poly(sorbitol-gluconic acid), 5%-6% of the injected dose of radiolabel was eliminated as 14CO2 and about 85% in the urine and faeces. Administration of 59Fe-iron-poly(sorbitol-gluconic acid) complex (10 and 100 mg of iron/kg) resulted in a urinary and faecal excretion of about 18% and 40% of the given dose, respectively, during the first 4 days. Biliary excretion was low. The mean molecular weight of the biliary product after the iron complex was lower than that of the parent compound. Radiocarbon in tissues after 24 hours was negligible. Liver and bones accounted for most of the retained radioiron following 100 mg of iron/kg bodyweight of the 59Fe-iron complex with maximum levels of 27% and 12% of the injected dose, respectively, 4 days after dosing. Red cell incorporation of 59Fe attained a level of 16% at the end of 28 days.

Relative contribution of parenchymal and non-parenchymal cells to the hepatic distribution and metabolism of iron-poly(sorbitol-gluconic acid) complex in the rat.

The hepatic cellular distribution in rats of radioiron and radiocarbon after [14C-gluconic acid]-and 59Fe-labelled iron-poly(sorbitol-gluconic acid) complex, glusoferron (Ferastral), has been investigated. Following administration of the 59Fe-iron complex at a dose level corresponding to 10 mg of iron per kg bodyweight, the ratio of radioactivity per 10(8) cells in parenchymal (P) and non-parenchemal (NP) cell fractions, the P/NP ratio, was 3.0 after 24 hours and rose to 10.4 at day 14. After 100 mg/kg the ratio was 0.9, 10.5 and 5.7 at day 1, 4 and 14, respectively. Radiocarbon content in the different cell compartments fell steadily throughout. Radioiron from 59Fe-iron-poly(sorbitol-gluconic acid) complex was shown to be incorporated into whole liver 59Fe-ferritin. In vitro uptake studies with the different liver cells were also performed. Parenchymal cells were found to be more active than non-parenchymal cells with regard to cellular uptake of radiolabel from both iron complex and polymeric ligand without iron.

Distribution of 59Fe-labelled iron-poly(soribitol-gluconic acid) complex in normal and anaemic rats.

An iron carbohydrate complex, iron-poly(sorbitol-gluconic acid), Ferastral, was labelled with 59Fe, and its distribution in rats was studied. The animals were intramuscularly treated with a dose of 10 mg of iron/kg. Three groups of animals were used: group A: non-anaemic and group B: anaemic rats, both kept on iron-deficient diet, and group C: non-anaemic rats kept on iron-supplemented diet. Urinary and faecal excretion, distribution in the body and incorporation in blood of the 59Fe was followed up to 28 days. The total excretion after that time was 15%. There was a rapid initial phase followed by a slower continuous one. After 28 days group A had 25, group B 13 and group C 40% of the given dose remaining at the site of injection. The corresponding values in liver after 28 days were 7, 4 and 17% of the given dose, respectively. In blood a continuous increase was observed. At 28 days after administration 26, 43 and 17% of the given dose had been incorporated in the red blood corpuscles of the respective groups. These results show that the iron complex is absorbed from the site of injection and is utilized for haemoglobin synthesis. They also show that the disposition of the complex is influenced by the iron content of the diet.

Disposition in rats of the carbohydrate polymer in Ferastral--an iron-poly (sorbitol-gluconic acid) complex.

The disposition and pharmacokinetics in rats of 14C-sorbitol-Ferastral has been studied as an initial step towards elucidating the metabolic fate of the polymeric organic moiety. The period of time studied was 24 h. Following i.v. administration of a dose corresponding to 10 mg/kg of iron approximately 60% of the isotope was found in the urine after this period of time. A further 3% was demonstrated in the faeces whilst the expired air accounted for about 10% in the form of 14CO2. Thus, a relatively large proportion of the radiolabel was promptly excreted via the kidneys whilst the expired air and probably bile constituted secondary excretion routes. The physico-chemical nature of the urinary product was similar to the parent carbohydrate compound. The residual 14C radioactivity was distributed mainly between the liver, which contained approximately 45% of the retained label, carcass with 36% and large intestine with 7%. The plasma disappearance pattern was biphasic. Similar experiments with the 14C-sorbitol polymer starting material were performed for purposes of comparison.