Effect of Age on Distribution of Zidovudine (Azidothymidine) into the Cerebrospinal Fluid of Macaca nemestrina

The brain tissue is an important target for anti-HIV drug therapy. Since the permeability of the blood–brain and blood–cerebrospinal fluid (CSF) barriers may differ between neonates and adults, we have determined the effect of age on the distribution of zidovudine (ZDV or azidothymidine) into the CSF in the macaque (M. nemestrina). Five newborn macaques were administered ZDV (iv bolus, 5 mg/kg) at various ages (2 days to 4 months). Both CSF (cisternal) and venous blood samples were obtained at approximately 60 and 90 min after drug administration. In another series of experiments, adult female macaques received ZDV as either an iv bolus (5 and 10 mg/kg) or an infusion for at least 12 hr. CSF (lumbar) and venous blood samples were obtained at approximately 60 and 90 min after iv bolus and at more than 12 hr after iv infusion. ZDV concentration in the CSF and the plasma samples was determined by high-performance liquid chromatography. The CSF/plasma concentration ratio of ZDV in the newborn and adult macaques, after iv bolus administration, was independent of time. In addition, no significant (P > 0.05) difference was observed in the pooled iv bolus ZDV CSF/plasma concentration ratio between the adult group (0.236 ± 0.058) and the newborns (0.213 ± 0.039). Moreover, the ZDV CSF/plasma concentration ratio in the adults and the newborns, after iv bolus administration, was found not to be significantly (P > 0.05) different from the ratio obtained at steady state in the adults (0.224 ± 0.094). These data indicate that the distribution of ZDV into the CSF in macaque neonates and adults is similar.     

Decreased effectiveness of chelation therapy with time after acute cadmium poisoning

The effect of increasing the time interval between cadmium (Cd) exposure and chelation therapy was studied in male Swiss Webster mice. The following chelating agents were administered ip at 0, 2, 12, 36, and 72 hr after giving radioactive Cd (1 mg Cd/kg, iv): diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), and 2,3-dimercaptosuccinic acid (DMSA). Daily elimination of Cd into urine and feces was determined for 5 days after which time the mice were killed, and the concentration of Cd was determined in various organs. In most of the tissues examined, including kidney and liver, only administration of chelators immediately after Cd significantly reduced tissue Cd concentrations. The mice treated immediately after Cd administration excreted between 50 and 75% of the Cd into urine in the first 24 hr compared to 0.1% excreted by controls. Treatment at later times (2 to 72 hr) significantly increased Cd excretion but the magnitude of the effect was far less than that seen in mice treated immediately after Cd. In a separate group of mice, the time course for the induction of metallothionein synthesis was determined by administering 1 mg Cd/kg iv at various times before death. Metallothionein concentration increased within 2 hr after Cd administration and reached a maximum within 8 hr. The results show that the length of time before initiating chelation therapy for Cd poisoning greatly influences the effectiveness of the therapy. Hepatic metallothionein may be responsible for this phenomenon.     

The Disposition of a Human Relaxin (hRlx-2) in Pregnant and Nonpregnant Rats

The pharmacokinetics and tissue distribution of a human relaxin were investigated after intravenous (iv) bolus administration to pregnant or nonpregnant rats. Human gene-2 relaxin (hRlx-2) serum concentrations after iv bolus administration were described as the sum of three exponentials. The pharmacokinetics were comparable in pregnant and nonpregnant rats. The serum clearance (CL) was 7.4–10.2 ml/min/kg at doses of 46–93 µg/kg and was linear in this range. The half-lives were 1.1–2.0, 15.1–16.4, and 53.7–67.9 min, respectively. The volume of the central compartment (V _c) was 48–79 ml/kg and the volume of distribution at steady state (V _ss) was 271–336 ml/kg. Increasing the dose to 463 µg/kg increased the dose-corrected area under the serum concentration–time curve and significantly decreased CL and Vss. The distribution of radioactivity in the tissues of pregnant rats was followed after iv bolus dosing with hRlx-2 internally labeled with ³⁵S-cysteine. Comparison of the extent of organ uptake of radiolabel after ³⁵S-hRlx-2 or ³⁵S-cysteine administration suggested that the kidneys were the principal site of uptake; the liver was of secondary importance. In perfusion experiments utilizing livers isolated from pregnant or nonpregnant rats, 36–52% of the dose of hRlx-2 was cleared from the perfusate in 2 hr. These studies showed that the pharmacokinetics of hRlx-2 in rats appeared to be unaffected by pregnancy and suggested that the kidneys and liver both play a role in the elimination of hRlx-2.     

Pharmacokinetics of the anti-AIDS drug 2',3'-dideoxyinosine in the rat

The pharmacokinetics of 2',3'-dideoxyinosine (ddlno) was examined in the male Fischer 344 rat using reversed phase HPLC with UV and radiochemical detection. Following iv doses of 12, 25, and 100 mg/kg, the parent drug was rapidly eliminated from plasma (mean residence time, 6.3 min; systemic clearance, 64 ml/min/kg). The mean terminal elimination half-life was 28 min and the volume of distribution at steady state was 0.39 liter/kg. Orally administered [3H]ddlno (100 mg/kg) was not significantly bioavailable in the rat, with only 8-11% of the dose absorbed as the parent compound over a 2 hr period. Peak plasma drug concentrations occurred 10 to 20 min following oral administration. Solution stability data suggested that ddlno was unstable at gastric pH (pH 1, t1/2 less than 30 sec). However, elevation of gastric pH with sodium bicarbonate prior to oral administration of ddlno was not effective in increasing the bioavailability of the parent drug. The drug and its metabolic products were extensively distributed into rat tissue 48 hr after iv or oral administration. Following iv infusion of [3H]ddlno to steady state conditions, the highest tissue-to-plasma ratios of radioactivity were found in the kidney (2.2), liver (1.7), and spleen (1.5). Renal clearance accounted for 99% of the eliminated dose. Liver perfusion studies showed that ddlno was not subject to significant hepatic clearance (less than 10%) and that the metabolism was not inducible with phenobarbital.     

Disposition and metabolism of carbovir in mice dosed intravenously or orally

To determine the disposition of carbovir and [3H]carbovir in mice, HPLC and thin-layer chromatographic assays were developed and mice were dosed iv and by gavage. Carbovir had no lethal effect at iv doses up to 500 mg/kg and was stable for 24 hr in mouse plasma at temperatures ranging from 0-37 degrees C. Binding to plasma proteins was minimal. Following an iv dose of 500 mg/kg of carbovir or [3H] carbovir, elimination phases with half-lives of 26-37 min (alpha) and 206-330 min (beta) were observed for plasma. For mice dosed with 27 mg/kg of [3H]carbovir, however, only a single phase with a half-life of 17 min was noted. Of several tissues examined, kidney contained the highest concentration of radioactivity. For the high dose, 19.0 +/- 2.6% was excreted in the urine in 24 hr as unchanged carbovir and 42.2 +/- 2.4% as metabolites; for the low dose, 54.5 +/- 6.1% was excreted as carbovir and 26.5 +/- 5.0% as metabolites. When mice were dosed orally with 500 mg/kg, plasma concentrations of carbovir were low. The initial plasma half-life for carbovir was 69 min; the terminal half-life was 822 min. Urinary excretion of unchanged carbovir was 21.3 +/- 7.1%. These results indicate that clearance of high doses of carbovir is limited and that its absorption is poor after oral dosing.     

Comparison of pharmacokinetics and tissue disposition of an antisense phosphorothioate oligonucleotide targeting human Ha-ras mRNA in mouse and monkey

The plasma pharmacokinetics and tissue disposition of ISIS 2503 were studied in mice following single and multiple bolus intravenous (iv) injections of 1-50 mg/kg, and in monkeys following single and multiple 2-h iv infusions of 1-10 mg/kg and bolus iv injections of 1 mg/kg of ISIS 2503. ISIS 2503 and its metabolites were measured in plasma, urine, and tissues using solid-phase extraction followed by capillary gel electrophoresis (CGE). In both species, the plasma clearance of ISIS 2503 was characterized by rapid distribution to tissues, and to a lesser extent, metabolism. The plasma clearance in mice was at least two-fold more rapid than in monkeys at equivalent doses. The plasma disposition (t1/2) increased with dose. The highest concentrations of oligonucleotide were consistently observed in the kidney and liver in both species. At equivalent doses, tissue concentrations in monkeys were much higher than tissue concentrations in mice. Urinary excretion of total oligonucleotide was a minor elimination pathway in both species at doses < 10 mg/kg. However, urinary excretion of total oligonucleotide in mice was increased to 12-29% as dose increased from 20 to 50 mg/kg.     

Cisplatin-induced loss of kidney copper and nephrotoxicity is ameliorated by single dose diethyldithiocarbamate, but not mesna.

Platinum, copper, and zinc concentrations in kidney and liver were monitored following administration of cis-diamminedichloroplatinum (Cisplatin, CDDP) alone or in combination with diethyldithiocarbamate (DDC) or mercaptoethanesulfonate (mesna). Compounds were administered in saline to F344 female rats as single bolus ip doses: 7.5 mg CDDP/kg body wt; 500 mg DDC/kg body wt 1 hr after CDDP; and 100 mg mesna/kg body wt 1 hr before CDDP, at the same time as CDDP, or 1 hr after CDDP. Tissues were collected at 4 hr, 1 day, 4 days, and 7 days post-CDDP dosing. CDDP alone produced significant increases in blood urea nitrogen (fourfold) and plasma creatinine (threefold) concentrations by Day 4. Concurrent with the toxicity, CDDP lowered kidney copper (-71%) by Day 4, but had little effect on liver copper except in copper-pretreated rats. Copper-pretreated rats initially had a twofold higher kidney copper concentration and a fourfold higher liver copper concentration, but by Day 4, CDDP lowered copper concentrations in both organs to near the noncopper-treated levels. Platinum in kidney and liver rose 72-100% of peak levels within 4 hr post-CDDP and was relatively stable throughout the 7-day test period. Kidney zinc rose significantly by day 4 only in CDDP-treated rats. DDC protected against the kidney toxicity of CDDP and markedly changed kidney copper loss. Within 4 hr, DDC reduced kidney copper 60% while increasing kidney platinum to the highest concentration of any of the treatments. By Day 4, DDC-treated rats had approximately 50% lower kidney platinum while copper returned toward control levels. A single dose of mesna did not significantly protect against CDDP nephrotoxicity and had little effect on kidney platinum, copper, or zinc. The patterns of copper loss and toxicity from CDDP alone or with DDC suggest that copper be further evaluated for its role in the mechanism of CDDP cytotoxicity.     

Role of intestinal metallothionein in absorption and distribution of orally administered cadmium

The effects of mucosal metallothionein (MT) preinduced by Zn on the intestinal absorption and tissue distribution of Cd were studied. 109CdCl2 was administered to control and Zn-pretreated rats. The total amount of Cd distributed to the liver and the kidney in the group pretreated with 100 mg/kg of Zn was about 70% that of the control group. In the control group, the Cd concentration in the intestinal mucosa reached a maximum 16-24 hr after its administration and then gradually decreased with time, unlike that in the liver and the kidney. The concentration of intestinal Cd in the pretreated group reached a maximum earlier than it did in the control group and most of the Cd was in the MT fraction. Pretreatment with Zn (100 mg/kg or higher, po) caused a reduction in the Cd concentration in the liver and an increase in the kidney. Pretreatment with Zn (5 X 10 mg/kg, sc) or Cd (5 mg/kg, po) also increased renal Cd concentration. This was effective at 24 hr but not at 0.5 hr after pretreatment. These effects of pretreatment with Zn (100 mg/kg, po) on tissue distribution of Cd were also observed after an intraintestinal injection of Cd but not after an iv injection. The results indicate that MT in intestinal mucosa plays a significant role not only in the absorption of Cd but also in its transport to the kidney.     

Distribution of 2-ethylhexanoic acid in mice and rats after an intraperitoneal injection

The distribution of 2-ethylhexanoic acid (2-EHA), a new wood preservative agent was studied in mice and rats. 2-14C-EHA in rat blood, brain, liver and kidney was quantitated by liquid scintillation analysis and by wholebody autoradiography in mice. A single intraperitoneal dose of 2-14C-EHA was injected in both species. Animals were sacrificed 30 min., 2 and 6 hr after the administration of 2-14C-EHA in autoradiography experiments. The highest uptake of 2-14C-EHA was observed in the liver, kidney and blood of mice. In contrast, low uptake of 2-14C-EHA was seen in the brain. 2-14C-EHA was well detectable in the olfactory bulb and in the salivary gland. In rats, at 2 hr after administration the highest concentration of 2-14C-EHA occurred in blood (0.3% of the total dose/g tissue). The radioactivity in the liver (0.2%) and kidney (0.1%) was also relatively high. The concentration of 2-14C-EHA was low in the brain (0.02%). By 6 hr. the radioactivity had decreased rapidly and was hardly measurable at 24 hr after the administration. The results suggest that 2-EHA is rapidly cleared from the tissues.     

Species and dose differences in the accumulation of imipramine by mammalian lungs

Adult male mice, guinea pigs, rabbits, and rats were injected ip with 14C-imipramine (IP) at doses of either 10 or 50 mg/kg and killed 15 min or 12 hr later. Plasma, lung, liver, and kidney were analyzed for total radioactivity and for IP and desmethylimipramine (DMI). Neither mouse nor guinea pig lungs accumulated IP-derived 14C relative to the other tissues at either dose or time. Indeed, tissue/plasma (T/P) ratios for liver in these species exceeded those for lung. Rabbit and rat lung did not selectively accumulate radioactivity at either time point after 10 mg/kg or at 15 min after 50 mg/kg. However, 12 hr after 50 mg/kg, rabbit and rat lungs contained significantly more radioactivity than other tissues, lung T/P ratios being 3-4 times those of liver and kidney. Most of the radioactivity retained in rat lung was present as DMI (approximately 70%), whereas the three other species retained predominantly unchanged IP (60-80%). In rats, increasing the IP dose from 10 to 100 mg/kg resulted in a 10-fold increase in radioactivity in plasma, 3-fold increases in liver and kidney, and a 20-fold increase in lung. Studies with lung slices revealed that although all species avidly accumulated IP from the medium, all species but rabbit rapidly released the drug by efflux into drugfree medium. The data suggest that only rat and rabbit lung retain significant amounts of IP after administration of large doses to intact animals, and probably by different mechanisms. Rabbit lung retains mainly unchanged IP due to slow efflux of the drug from the lung whereas the rat rapidly demethylates IP to DMI and this metabolite is then retained by the lung.     

Distribution,elimination, metabolism and bioavailability of hexamethylenebisacetamide in rats

Summary Hexamethylenebisacetamide (HMBA), an in vitro differentiating agent, was studied for its pharmaco-dynamic actions in animals. Plasma stability, organ distribution, excretion, oral bioavailability, and estimates of pharmacokinetic parameters and acute lethality were determined in rats. The single dose intraperitoneal LD₅₀ was greater than 3000 mg/kg in both mice and rats. The drug was stable in plasma from several different species during an 8 h in vitro incubation at 37°C. Following a single intravenous (iv) bolus injection (1000 mg/kg) to rats, HMBA was removed from the plasma with a half time of 2.2 ± 0.5 h, and 65 ± 8% of the dose was excreted unchanged in the urine during the first 24 h after dosing. During an 8 h iv infusion, plasma concentrations of 4 mM were easily maintained with no apparent adverse effects. Drug was uniformly distributed, with highest concentrations found in thymus, kidney, liver, and lymph node throughout the first 24 h after a single iv bolus dose. In vivo metabolism was very small, and the presence of apparent metabolites was undetectable until 48 h after iv administration. Oral bioavailability was good (32%), with peak plasma concentrations of 2 mM achieved one hour after oral administration. After oral dosing urinary excretion and plasma decay were comparable to similar data obtained after iv dosing.     

Species differences in kidney necrosis and DNA damage, distribution and glutathione-dependent metabolism of 1,2-dibromo-3-chloropropane (DBCP)

Species differences and mechanisms of 1,2-dibromo-3-chloropropane (DBCP) nephrotoxicity were investigated by studying DBCP renal necrosis and DNA damage, distribution and glutathione-dependent metabolism in rats, mice, hamsters and guinea pigs. Extensive renal tubular necrosis was observed in rats 48 hr after a single intraperitoneal administration (21-170 mumol/kg) of DBCP. Significantly less necrosis was found in mice and guinea pigs, whereas no renal damage was evident (less than 680 mumol/kg) in hamsters. The activation of DBCP to DNA damaging intermediates in vivo, as measured by alkaline elution of DNA isolated from kidney nuclei 60 min. after intraperitoneal injection of DBCP, was compared in all four species. Distinct DNA damage was detected in rats, mice and hamsters as early as 10 min. after administration of DBCP and within 30 min. in guinea pigs. Rats and guinea pigs showed similar sensitivity towards DBCP-induced DNA damage (extensive DNA damage greater than 21 mumol/kg DBCP), whereas in mice and hamsters a 10-50 times higher DBCP dose was needed to cause a similar degree of DNA damage. Renal DBCP concentrations at various time-points (20 min., 1, 3 and 8 hr) after intraperitoneal administration (85 mumol/kg) revealed that the initial (20 min.) DBCP concentration was substantially higher in rats and guinea pigs compared to the other two species. Furthermore, kidney elimination of DBCP occurred at a significantly lower rate in rats than in mice, hamsters and guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute exposure to cadmium causes severe liver injury in rats

The acute cardiotoxicity of Cd was studied in rats injected iv with 3.9 mg Cd/kg (LD99). Electrocardiogram, blood pressure, and heart rate were recorded intermittently from 9 hr after Cd administration until death. No changes were observed in cardiac indices. Microscopic examination of the major tissues revealed histologically normal myocardium but severely damaged liver. To evaluate further the observed hepatotoxic effects of Cd, time course (1 to 10 hr after 3.9 mg Cd/kg, iv) and dose-response (10 hr after 0.9 to 3.9 mg Cd/kg, iv) studies were conducted. Liver was examined for histopathologic changes; plasma enzyme activities of aspartate (AST) and alanine (ALT) aminotransferases and alkaline phosphatase (AP) were determined to assess liver damage. Pronounced eosinophilia, hepatocyte swelling, and an increase of mitotic figures in hepatocytes were present within 1 hr after Cd. Increased AST and ALT activities were also observed, but AP activity and plasma glucose concentration were unchanged. At later times, severe liver injury was evidenced by necrosis of hepatocytes, striking elevation of serum enzymes (AST, ALT, and AP), and a 50% decrease in plasma glucose concentration. Doseresponse data indicated that doses greater than 1.1 mg Cd/kg produced pathologic changes similar to those observed in the time course study 1 hr after 3.9 mg Cd/kg. Doses above 3.5 mg Cd/kg caused massive hepatic necrosis and increased ALT, AST, and AP activities 60-, 100-, and 3-fold, respectively. A 50% decrease in plasma glucose concentration was also observed at doses above 2.9 mg Cd/kg. These results do not suggest that Cd is cardiotoxic after acute exposure, but rather that the liver is a major target organ for acute Cd toxicity.     

Validation of high-performance liqid chromatography method to determine epirubicin and its pharmacokinetics after intravenous bolus administration in rats

We investigated the pharmacokinetics of epirubicin, an anthracycline derivative antibiotics, after intravenous (i.v.) bolus administration in rats. To analyze epirubicin levels in the plasma, bile, urine and tissue samples, we developed an high-performance liqid chromatography (HPLC)-based method which was validated for a pharmacokinetic study by suitable criteria. The plasma concentration of epirubicin after i.v. bolus administration was rapidly disappeared within 10 min from the blood circulation. The mean plasma half-lives at α phase (t_1/2α) when administered at the dose of 2, 5, 10, 25 and 50 mg/kg were 2.14–2.61 min. The values of t_1/2β at the corresponding doses increased two folds (from 150 to 291 min) with increasing doses. The CL_t values significantly decreased with the increase in dose. In contrast, V_dss values increased about 1.5 times with the increase in dose from 2 to 50 mg/kg. Of the various tissues, epirubicin mainly distributed to the kidney, lung, heart and liver after i.v. bolus administration. The epirubicin concentrations in various tissues at 24 h after i.v. bolus administration were below 1.0 μg/g tissue. Epirubicin was excreted largely in the bile after i.v. bolus administration at the dose of 2, 10 and 50 mg/kg. The cumulative amount of epirubicin in the urine 72 h after dosage represented 20 % of the amount excreted in the bile 12 h after high dosage, indicating that i.v. administered epirubicin was mainly excreted in the bile. In conclusion, epirubicin was rapidly cleared from the blood circulation and transferred to tissues such as the kidney and liver 2 h after i.v. bolus administration. Moreover, the majority of epirubicin appears to be excreted in the bile by 12 h after i.v. bolus administration.     

Metabolic disposition and irreversible binding of phencyclidine in rats

The metabolic disposition of [¹⁴C]phencyclidine ([¹⁴C]PCP) was examined in rats after intratracheal, ip or iv drug administration. [¹⁴C]PCP absorption by the lung was related to time biphasically after intratracheal administration. At 1 hr after ip administration of [¹⁴C]PCP (1.8 mg/kg), the concentration of radioactivity in various tissues decreased (in descending order) in the liver, fat, kidney, lung, testes, spleen, heart, and brain. High levels of radioactivity were also detected in the urine and feces, but not in the blood. The radioactivity accumulated by the liver, lung, and kidney was only partially removed by repeated extraction with 80% methanol, indicating the in vivo formation of PCP reactive metabolite which bound with protein irreversibly. Incubation of [¹⁴C]PCP with rat liver microsomes corroborated that a PCP reactive metabolite was formed. Although hepatic benzpyrene hydroxylase activity decreased significantly after rats were pretreated with PCP, neither microsomal cytochrome P-450 content nor aniline hydroxylase and p-chloro-N-methyl-aniline demethylase activities in lung, liver, and kidney were altered. After a single iv dose of [¹⁴C]PCP (0.9 mg/kg), biliary radioactivity peaked at about 30 min. Hydroxylated PCP and corresponding glucuronides represented the bulk of the biliary radioactivity. When radioactive bile from a rat pretreated with [¹⁴C]PCP was administered to a recipient rat intragastrically, radioactivity was found in the bile, indicating enterohepatic recycling of PCP.     

Early changes in the tissue distribution of cadmium after oral but not intravenous cadmium exposure

The kinetics of 109Cd distribution in tissues of male and female mice were measured at intervals of 5 min to 15 days after oral (100 micrograms Cd/kg; by gavage) or intravenous (1 micrograms Cd/kg; i.v.) administration of 109CdCl2. Unexpectedly, the ratio of 109Cd in liver to that in kidneys was greater than or equal to 10 within 1 h after administration by either route. However, after 4 h, route-dependent differences in distribution between liver and kidney became apparent. In mice receiving oral cadmium, the liver:kidney 109Cd ratio decreased with time to approximately 4 at 72 h after gavage. In contrast, in mice receiving IV cadmium, the liver:kidney 109Cd ratio remained high and relatively constant during the same time period. The time-dependent decrease in the liver:kidney 109Cd ratio after oral cadmium administration was caused by a 4-5-fold increase in cadmium content of the kidney that occurred between 30 min and 72 h after oral but not i.v. administration. During this time, there was no change in cadmium distribution in subcellular fractions of either liver or kidney. These results could be explained by the existence of 2 separate pathways for cadmium deposition after oral exposure. Early after exposure, cadmium may leave the intestine, bind to serum albumins or other high molecular weight proteins, and accumulate primarily in liver, as is also observed after IV cadmium administration. With time, cadmium may leave the intestinal mucosa bound to metallothionein and deposit primarily in the kidney. The different pathways of deposition after oral vs. i.v. exposure may in part explain why acute parenteral cadmium exposure causes liver toxicity, but chronic oral exposure causes renal toxicity.     

Disposition in animals of a new anti-HIV agent: 2',3'-didehydro-3'-deoxythymidine

The pharmacokinetics and CNS penetration of the anti-human immunodeficiency virus agent 2',3'-didehydro-3'-deoxythymidine have been examined in CD-1 mice. The drug was rapidly cleared from plasma with a terminal half-life of 17 min after an iv bolus dose at 25 mg/kg. Oral absorption of 2',3'-didehydro-3'-deoxythymidine was rapid and complete (98% bioavailable) with plasma levels approximately the same as those measured after iv administration. Estimates of the total body clearance and apparent volume of distribution were 43 ml/hr and 19 ml, respectively. In the mouse, entry into the central nervous system was rapid but the concentrations were somewhat low. However, drug concentrations which were reported to be effective in inhibiting replication of the virus in cell culture, greater than 0.01 microM, could be measured in the brain after a single oral dose at 25 mg/kg. A study to examine the urinary excretion of the drug in CD rats, beagle dogs and cynomolgus monkeys showed that 2',3'-didehydro-3'-deoxythymidine was primarily renally excreted unchanged.     

Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.     

Disposition of ethimizol, a nootropic drug, in rats and mice

The pharmacokinetics of ethimizol, a nootropic drug, were studied in rats and mice using [2-14C]-4,5-di(methylcarbamoyl)-1-ethyl-imidazole. Autoradiography in mice injected iv showed a rapid and homogeneous distribution of the label into the tissues, brain included, and its excretion by the urinary pathway. The determination of ethimizol in plasma, organs, and excreta was based on combined extraction and the TLC procedure. In rats, the elimination half-life of ethimizol after iv administration of 10 mg/kg was 25 min, and its distribution volume was 1.4 liters/kg. The tissue/plasma concentration ratio for organs investigated was 1 immediately after iv administration, with a subsequent gradual increase. Based on this, saturable tissue binding of ethimizol in the liver, kidney, and brain was suggested. The drug was almost completely absorbed after administration, yet its systemic availability was only 32%. The brain uptake index of ethimizol was 101% as compared to 3H2O. Ethimizol was eliminated by metabolism. The labeled metabolites were predominantly excreted in the urine.     

Metallothionein-null and wild-type mice show similar cadmium absorption and tissue distribution following oral cadmium administration

Cadmium (Cd) is an environmental pollutant and is toxic to many tissues. Food is the primary source of Cd exposure for the general population. Metallothionein (MT), a cysteine-rich, Cd-binding protein, plays an important role in Cd detoxication. However, the role of MT in Cd absorption and distribution is still controversial. For example, some reports assert that MT in the intestine decreases Cd absorption and increases its distribution to the kidney, relative to the liver. Therefore, to further clarify the role of MT in Cd absorption and tissue distribution, MT-I/II knockout (MT-null) mice and their parental background wild-type mice were given a single dose of (109)Cd (1-300 micromol/kg po or 0.1-30 micromol/kg iv). Cd content in 15 organs was determined 4 h after Cd administration by gamma scintillation spectrometry. Approximately 60% of the Cd administered iv was retained in liver, and about 5% was retained in kidney in both MT-null and wild-type mice. The distribution of iv administered Cd was independent of dose. In contrast, when administered po, approximately 0.15% of the lowest dose (1 micromol/kg) and 0.75% of the highest dose (300 micromol/kg) was detected in the liver of both MT-null and wild-type mice. Similarly in kidney, approximately 0.05% of the dose was detected after the lowest dose and about 0.15% after the higher doses in both MT-null and wild-type mice. In summary, this study demonstrates that the absorption and initial distribution of orally administered Cd is dose dependent but is not influenced by MT.