Developmental Neurotoxicity Evaluation of Orally Administered Isopropanol in Rats

Isopropanol was administered by gavage to timed-mated rats fromGestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administeredwere 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg.The dams were allowed to deliver and body weights and food consumptionwere recorded during gestation and lactation. Pups were counted,examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36,49, and 68. Litters were culled to eight pups (4:4 or 5:3 sexratio) on PND 4 and litters without acceptable numbers of maleand female pups were eliminated from the study. Pups were weanedon PND 22, and two pups from each litter and their dams werekilled. Six of these pups from each dose group were perfusedin Situ for histopatho logical examination of the central andperipheral nervous sys tem. Brains of the remaining pups weredivided into four regions and weighed. Maternal liver and kidneyweights were re corded. Weaned pups were assessed for day oftestes descent or vaginal opening and for motor activity onPNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and60; and active avoidance on PNDs 60–64. These pups wereeuthanized and examined on PND 68. One high-dose dam died onPND 15, but there were no other clinical observations or effectson maternal weight, food consumption, or gestation length. Pupsurvival, weight, sex ratio, and sexual maturation were unaffected.There were no biologically significant findings in the behavioraltests, no changes in organ weights, and no pathological findingsthat could be attributed to isopropanol exposure. In conclusion,there was no evidence of developmental neurotoxicity associatedwith isopropanol exposure as high as 1200 mg/kg/day.     

Isopropanol 13-Week Vapor Inhalation Study in Rats and Mice with Neurotoxicity Evaluation in Rats

This study was conducted to evaluate the possible subchronictoxicity as well as neurobehavioral effects of isopropanol,a widely used industrial and commercial solvent. Five groups,each containing 10 Fischer 344 rats/sex and 10 CD-I mice/sex,were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanolvapor at concentrations of 0 (control), 100, 500, 1500, or 5000ppm. An additional 15 rats/sex were assigned to the 0, 500,1500, and 5000 ppm groups for assessment of neurobehavioralfunction. No exposure-related mortalities occurred during thestudy. The narcotic effects of isopropanol were noted only duringexposures at 1500 and 5000 ppm. These signs, noted during exposures,were typically absent following exposures. The only clinicalsigns observed following exposures included swollen perioculartissue, perinasal encrustation, and ataxia for rats of the 5000ppm group. Neurobehavioral evaluations indicated no changesin any of the parameters of the functional observational battery;however, increased motor activity for female rats in the 5000ppm group was noted at Weeks 9 and 13. Decreases in body weightand body weight gain were observed for rats of the 5000 ppmgroup at the end of the first week of exposure. During the remainingweeks, increases in body weight and/or body weight gain wereobserved for rats of the 1500 and 5000 ppm groups. No exposure-relatedeffects on body weight were noted for male mice; however, increasedbody weight and body weight gain were observed for female miceof the 5000 ppm group. Increases or decreases in food and waterconsumption generally corresponded to changes in body weightand body weight gain. Various changes in clinical pathologyparameters were observed for rats and female mice of the 5000ppm group. The only organ weight effect noted was an increasedrelative liver weight in both sexes of rats of and female miceof the 5000 ppm group. At necropsy, three were no gross lesionsdetermined to be exposure related. Furthermore, the only microscopicchange observed was hyaline droplets within the kidneys of allmale rats (including controls). The size and frequency of thehyaline droplets were increased for the isopropanol exposuregroups compared to the control group. These differences werenot clearly concentration related, although this microscopicchange was most pronouced in the high-concentration group. Neuropatholo0gicexamination revealed no exposure-related lesions in the centralor peripheral nervous system of exposed rats. Thus, repeatedexposures to isopropanol for 13 weeks produced toxic effctsonly at the highest concentration and a kidney change in malerats of unknown biological significance.     

Teratologic Evaluation of Orally Administered Nitrapyrin in Rats and Rabbits3 1

Teratologic Evaluation of Orally Administered Nitrapynn in Ratsand Rabbits.BERDASCO, 2N.M., LOMAX, L.G., ZIMMER, M. A., ANDHANLEY, T. R., JR. (1988). Fundam Appl Toxicol 11, 464—471.Pregnant Fischer 344 rats and New Zealand White rabbits wereorally administered 0, 5, 15, or 50 mg nitrapyrin/kg/day onGestation Days 6 through 15 (rats) or 0, 3, 10, or 30 mg/kg/dayon Gestation Days 6 through 18 (rabbits). In rats, 50 mg/kg/dayproduced slight histopathologic changes in the livers of pregnantfemales. Fetal examination revealed no evidence of fetotoxicityor teratogenicity among rats at dose levels up to 50 mg/kg/day.Among rabbits, a significant depression in maternal weight gainand increased absolute and relative liver weights were observedat 30 mg/kg/day. An increased incidence of crooked hyoid boneamong fetal rabbits in the 30 mg/kg/day dose group was consideredindicative of fetotoxicity but not 3 teratogenicity. Thus, administrationof nitrapyrin was not teratogenic at dose levels up to 50 mg/kg/dayin rats and 30 mg/kg/day in rabbits     

Evaluation of the Immunotoxicity of Orally Administered 2-Methoxyacetic Acid in Fischer 344 Rats

Evaluation of the Immunotoxicity of Orally Administered 2-MethoxyaceticAcid in Fischer 344 Rats. SMIALOWICZ, R. J., RIDDLE, M. M.,ROGERS, R. R., COPELAND, C. B., LUEBKE, R. W., AND ANDREWS,D. L. (1991). Fundam. Appl. Toxicol. 17, 771–781. We previouslydemonstrated that the glycol ether 2-methoxyethanol (ME) isimmunotoxic in the rat. In this study, the immunotoxicity of2-methoxyacetic acid (MAA), the principal metabolite of ME,was evaluated in adult male Fischer 344 rats. Rats were dosedby gavage with MAA on 10 consecutive days at dosages rangingfrom 50 to 200 mg/kg/day. Thymic involution, in the absenceof body weight loss, was observed at 100 and 200 mg/kg/day MAA.Lymphoproliferative responses to the mitogens concanavalin A,phytohemagglutinin, and pokeweed mitogen were also reduced atthese dosages. The in vitro generated cytotoxic T lymphocyteresponse was reduced at 200 mg/kg/day MAA. The mixed lymphocytereaction and natural killer cell activity were unaffected byexposure to MAA. Enumeration of splenic lymphocyte populationsrevealed a reduction in the percentage of W3/25-positive cellsat 100 and 150 mg/kg/day and an increase in the percentage of0X39-positive cells at 200 mg/kg/day; however, no changes inthe absolute number of either of these subsets were observed.The plaque forming cell (PFC) response to trinitropheny-lipopolysaccharide(TNP-LPS) was suppressed at 50-200 mg/kg/day MAA, while thePFC response to sheep red blood cells (SRBQ was elevated at50 mg/kg/day. Immunization of rats with TNP-LPS or SRBC followedby oral exposure to MAA at 4 and 28 hr postimmunization resultedin the suppression of the PFC response to TNP-LPS and SRBC atdosages of 100 and 200 mg/kg and 200 and 400 mg/kg, respectively.Equal suppression of the PFC response to TNP-LPS was achievedat equimolar concentrations of ME and MAA. The effects of MAAon the immune system of the rat presented here are very similarto results reported from this lab for ME-induced immune alterations.These results, along with results of experiments in which ME-inducedsuppression of the PFC response to TNP-LPS was reversed by 4-methylpyrazole,an inhibitor of the oxidation of ME to MAA by alcohol dehydrogenase,indicate that MAA is the proximate immunotoxicant followingexposure to the glycol ether 2-methoxyethanol.     

Embryotoxicity and Fetotoxicity of Orally Administered Tridiphane in Mice and Rats

Embryotoxicity and Fetotoxicity of Orally Administered Tridiphanein Mice and Rats. HANLEY, T. R., Jr., JOHN-GREENE, J. A., HAYES,W. C., and RAO, K. S. (1987). Fundam. Appl. Toxicol. 8, 179–187.Tridiphane [2-(3,5-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane],a broad-leaf herbicide, was evaluated for its potential effectson mouse and rat embryonal and fetal development. Pregnant CF-1mice were given 0, 25, 75, or 250 mg tridiphane/kg/day on Days6 through 15 of gestation. Significant maternal toxicity wasobserved in both the 75- and 250-mg/kg/day dose groups. An increasedpercentage of females given 250 mg/kg/day showed implantationsites only after staining of the uterus, suggesting a toxiceffect on the embryo during the early stages of development,possibly secondary to maternal toxicity. Increases in some skeletalvariants were noted at the 75-mg/kg dose level; however, a teratogeniceffect was not observed. An additional group of mice was given250 mg/kg/day on Days 8 through 15 of gestation. Maternal toxicitywas also observed among these mice as manifested by significantlyelevated (+50%) liver weight; however, there was a substantialincrease in the number of females with full-term litters followingthis shorter dosing period. An increase in the occurrence ofcleft palate in these offspring associated with low fetal bodyweights was also observed. Pregnant Sprague-Dawley rats weregiven 0, 30, 100, or 200 mg/kg/day of tridiphane on Days 6 through15 of gestation. Maternal toxicity was observed among rats given200 mg/kg. Increased incidences of two minor skeletal variants,lumbar spurs and extra ribs, were observed in the 200-mg/kg/daydose group, and an increase in lumbar spurs was observed at100 mg/kg/day. Thus, tridiphane was embryotoxic and inducedcleft palate in mice only at the maternally toxic dose levelof 250 mg/kg/day. Slight fetotoxicity (increased skeletal variants)was observed in mice at 75 mg/kg, a dose which also produceda significant elevation of liver weight in the maternal animal.In rats, slight fetotoxicity was observed at the maternallytoxic dose of 200 mg/kg/day, and very slight fetotoxicity at100 mg/kg/day. Neither test species showed evidence of significantdevelopmental toxicity at dose levels which were not toxic tothe dam. Thus, the no observed effect levels (NOELs) for tridiphaneunder these test conditions were 25 and 30 mg/kg/day for miceand rats, respectively.     

The Developmental Toxicity of Orally Administered Theophylline in Rats and Mice

The Developmental Toxicity of Orally Administered Theophyllinein Rats and Mice. LIND-STRÖM, P., MORRISSEY, R. E., GEORGE,J. D., PRICE, C. J., MARR, M. C, KJMMEL, C. A., AND SCHWETZ,B. A. (1990). Fundam. Appl. Toxicol. 14, 167–178. Theophylline(THEO), a widely prescribed anti-asthmatic, was evaluated fordevelopmental toxicity. It was administered continuously onGestational Days 6 through 15 to pregnant Sprague-Dawley (CD)rats in the feed (0,0.15,0.30, or 0.40%) and to pregnant Swiss(CD-1) mice in the drinking water (0,0.075, 0.15, or 0.20%).Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day,while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats,maternal weight gain parameters (weight gain during gestationand treatment, as well as corrected weight gain) decreased at0.40%. While food consumption was lower only in the 0.40% treatmentgroup, water consumption was higher in all treated groups. Therewas a dose-related decreasing trend in gravid uterine weight.The number of live fetuses per litter decreased at 0.40% andthe average male and female fetal weight per litter decreasedat 0.30 and 0.40%. There was no increase in malformations. Inmice, maternal corrected body weight and weight gain duringgestation decreased at 0.15 and 0.20%, and weight gain duringtreatment and gravid uterine weight decreased at 0.20%. Waterconsumption was reduced by as much as 30-45% of controls at0.15 and 0.20%, respectively, while food consumption did notchange with THEO treatment There was an increase in percentageresorp-tions per litter and a decrease in the average male andfemale fetal weight per litter at 0.15 and 0.20%. An increasingtrend was noted for percentage malformed fetuses per litter,and percentage litters with externally malformed fetuses wereslightly increased in the mid- and high-dose groups. However,these increases were not statistically significant. In summary,there were developmental effects seen in rats at a dose (0.30%)that did not produce overt maternal toxicity, but the adversedevelopmental effects in mice were observed at doses that causedreduced maternal water consumption and body weight gain. Itis possible that water deprivation contributed to the effectsseen in mice after THEO treatment. For maternal toxicity, noobservable adverse effect levels (NOAELs) were 218 mg/kg forrats and 282 mg/kg for mice. NOAELs for developmental toxicitywere 124 mg/kg for rats and 282 mg/kg for mice. These NOAELsare approximately 10-to 30-fold greater than doses requiredto maintain humans on serum THEO concentrations that are clinicallyuseful.     

Disposition of Orally and Intravenously Administered Methyltetrahydrofuran in Rats and Mice

The disposition of [¹⁴C]methyltetrahydrofuran (¹⁴C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8–22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93–100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO₂. In rats the major route of excretion was exhaled CO₂ followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1–5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, ¹⁴C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the ¹⁴C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.     

The Developmental Toxicity of Orally Administered Oxytetracycline in Rats and Mice

The Developmental Toxicity of Orally Administered Oxytetracyclinein Rats and Mice. MORRISSEY, R.E., TYL, R.W., PRICE, C.J., LEDOUX,T.A., REEL, J.R., PASCHKE, L.L., MARR, M.C, AND KJMMEL, C.A.(1986). Fundam. Appl. Toxicol. 7, 434-443. Timed-pregnant CDrats and CD-1 mice were dosed by gavage with oxytetracyclinehydrochloride (OXT) in corn oil on gestational days (gd) 6-15(0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or2100 mg/kg/day for mice). Deaths among treated females occurredin a dose-related manner in all OXT dose groups (2-7%, mice;5-24%, rats), but no maternal deaths occurred in the vehiclecontrol groups. Significant dose-related decreases in maternalweight gain during treatment, as well as for corrected gestationalweight gain (i.e., maternal gestational weight gain minus graviduterine weight), were observed at all doses in rats but notin mice. Gravid uterine weight was reduced in a dose-relatedmanner only in mice, with the high-dose group significantlyreduced compared to the control group. At termination (gd 20,rats; gd 17, mice), the status of uterine implantation siteswas recorded and live fetuses were weighed. Fetuses were examinedfor external, visceral, and skeletal abnormalities. There wereno significant effects of OXT in either species on the incidenceof postimplantation loss (resorptions plus dead fetuses) ormalformations. In both species, there was a significant trendtoward reduced fetal body weight, and each group of rats receivingOXT was significantly reduced compared to the control group.Administration of OXT during organogenesis at doses exceedingthe therapeutic range for humans produced maternal and fetaltoxicity, but did not produce any treatment-related increasein malformations.     

Pharmacological and Toxicological Evaluation of Orally Administered Pyridostigmine in Dogs

Pharmacological and Toxicological Evaluation of Orally AdministeredPyridostigmine in Dogs. KLUWE, W. M., PAGE, J. G., TOFT, J.D., RIDDER, W. E., AND CHUNG, H. (1990). Fun-dam Appl. Toxicol.14, 40–53. Pyridostigmine bromide, a reversible cholinesteraseinhibitor, was administered orally (capsule gavage) to beagledogs (10–15 months of age) of both sexes once daily at5, 10, or20mg/kg for 14 days; every 8 hrat2 or 5 mg/kg for 28days; or every 8 hr at 0.05,0.5, or 2 mg/kg for 3 months aspart of its preclinical safety assessment. A small portion ofthe dogs receiving pyridostigmine for 3 months were allowedan untreated recovery period of an additional 3 months. Dailydoses of 10 or 20 mg/kg were lethal to some of the dogs whengiven for up to 14 days and caused severe intestinal distress,including diarrhea, emesis, and reddened feces in all animals.The cause of death was intestinal intussusception. Signs ofsystemic toxicity apparent at these doses included hypersalivationand tremors. Similar but less severe effects were produced by5 mg/kg per day, plasma cholinesterase activities were inhibitedby all three doses in a dose-related manner. Signs of toxicityin the 28-day and 3-month studies were generally limited tothe gastrointestinal tract and included diarrhea or soft stoolsand reddened or mucoid-containing stools; these signs appearedto reverse upon discontinuation of the drug. A single dog at2 mg/kg every 8 hr developed an apparent intussusception. Therewere no pathological changes in clinical chemistry, hematology,or urinalysis parameters associated with doses of 0.05, 0.5,or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-relatedlesions observed upon gross necropsy and microscopic evaluationof the major tissues and organs. Red blood cell (RBC) acetylcholinesterase(AChE) activities in the 3-month study were inhibited by approximately10,50, and 70% in the 0.05,0.5, and 2 mg/kg every 8-hr dosegroups, respectively, and these degrees of inhibition were maintainedthroughout the period of treatment. These data suggest thatprolonged oral administration of pyridostigmine at doses sufficientto cause profound and sustained inhibition of RBC AChE activity(i.e., as high as 70%) cause mainly local, gastrointestinaldistress related to altered intestinal motility. At the extreme,this can be manifested as a life-threatening intestinal intussusception.Systemic anticholinesterase effects (other than enzyme inhibition)were observed only at doses of 2 mg/kg and greater, while local(gastrointestinal) effects and inhibition of RBC AChE were observedat doses as low as 0.05 mg/kg.     

Evaluation of Orally Administered Highly Variable Drugs and Drug Formulations

Pharmaceutical Research -     

Comparative Immunosuppression of Various Glycol Ethers Orally Administered to Fischer 344 Rats

Oral dosing of adult male F344 rats with the glycol ether 2-methoxyethanol(ME) or its principal metabolite 2-methoxyacetic acid (MAA)results in the suppression of the primary plaque-forming cell(PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS).In the present study, the PFC response to TNP-LPS was used toevaluate the immunotoxic potential of ethylene glycol (EG) aswell as the glycol ethers 2-methoxyethyl acetate (MEA), 2-(2-methoxyethoxy)ethanol, bis(2-meth- oxyethyl) ether, 2-ethoxyethanol and itsprincipal metabolite 2-ethoxyacetic acid, 2-ethoxyethyl acetate,and 2-butoxyethanol relative to ME and MAA. Rats were immunizedwith TNP-LPS and then exposed 4 and 28 hr later to 50, 100,200, or 400 mg/kg of glycol ether or EG. Three days followingimmunization, the PFC response to TNP-LPS was determined. Inaddition to ME and MAA, only MEA, which was as effective asME, suppressed the PFC response to TNP-LPS. Concomitant administrationof the alcohol dehydrogenase inhibitor 4-methylpyrazole withME or MEA prevented suppression of the PFC response by theseglycol ethers. These results indicate that of the chemicalstested only ME, MEA, and MAA are immunosup pressive, and thatoxidative metabolism via alcohol dehydrogenase is necessaryfor ME- and MEA-suppression of the response to TNP-LPS.     

Developmental Toxicology Studies of Fluoxetine Hydrochloride Administered Orally to Rats and Rabbits

Pregnant Fischer 344 rats were given fluoxetine orally at doselevels of 0, 2, 5, or 12.5 mg/kg on Gestation Days (GD) 6–15;pregnant Dutch Belted rabbits were given 0, 2.5, 7.5, or 15mg/kg orally on GD 6–18. Cesarean sections were performedon rats and rabbits on GD 20 and 28, respectively. In rats,maternal toxicity was indicated at 12.5 mg/kg by depressionof weight gain and food consumption. Fetal viability, weight,and morphology were not affected at any dose level. Maternaland developmental No Observed Adverse Effect Levels (NOAELs)in the rat were 5 and 12.5 mg/kg, respectively. In rabbits,weight loss occurred at 2.5,7.5, and 15 mg/kg. Food consumptionwas also depressed at 7.5 and 15 mg/kg; abortions and maternalmortality occurred secondarily to anorexia and cachexia at 15mg/kg. Fetal viability, weight, and morphology were not affectedat any dose level. A NOAEL for maternal effects was not establishedin the rabbit; the NOAEL for developmental effects in the rabbitwas 15 mg/kg. Based on these data, fluoxetine did not exhibitany toxicity toward the developing rat or rabbit conceptus atdoses that were maternally toxic.     

Teratology Studies of Compound Lyn 171883 Administered Orally to Rats and Rabbits

Teratology Studies of Compound LY171883 Administered Orallyto Rats and Rabbits. HA-GOPIAN, G. S., HOOVER, D. M., AND MARKHAM,J. K. (1988). Fundam Appl Toxicol. 10, 672–681. The teratogenicpotential of the leukotriene antagonist LY171883, a novel antiasthmaagent, was investigated in CD rats and Dutch Belted rabbits.Mated female rats were dosed with 0, 10, 65, or 425 mg/kg/dayon gestation days 6 through 15 and killed on gestation day 20.Mated female rabbits were dosed with 0, 20, 65, or 200 mg/kg/dayon gestation days 6 through 18 and killed on gestation day 28.Maternal toxicity was indicated at 425 mg/kg in rats and 200mg/kg in rabbits by depressed body weight gain and food consumption.In the rabbit study four abortions occurred at 200 mg/kg, mostlikely secondarily to maternal toxicity. LY171883 did not causeembryo/fetal toxicity or teratogenicity in rats or rabbits atdoses up to and including those that were maternally toxic.     

Antisecretory Activities of Orally Administered Loperamide and Loperamide Oxide on Intestinal Secretion in Rats

Abstract— In-vivo experiments in the rat jejunum have been performed to compare the antisecretory effect of orally administered loperamide with the effect of its pro-drug, loperamide oxide. Both loperamide and loperamide oxide, administered orally, reduced the secretory effect of prostaglandin E₂ (32 ng min^?1, intra-arterially) in the jejunum and the colon. Differences between the two drugs as to time course and dose response can be seen. Loperamide oxide shows its antisecretory effect in the jejunum, and at a dose of 2 mg kg^?1 also shows its effect in the colon 1 h after administration. The effect was maximal after 2 h and decreased after 4 h. A dose-response relationship was demonstrated at 2 h in the jejunum and the colon. In comparison, the effect of loperamide started later, and a good dose-response relationship was not observed in the jejunum or in the colon, higher doses always appearing less effective than lower doses.     

Chronic (1-Year) Safety Evaluation of Ipazilide Fumarate, an Antiarrhythmic Agent, Administered Orally to Rats

Ipazilide fumarate (WIN 54177-4) is a chemically novel antiarrhythmicagent that prolongs ventricular refractoriness and possessesantiectopic activity. The compound is being developed as oraland iv therapy for ventricular and supraventricular arrhythmias.Since ipazilide therapy may require long-term use, a 1-yearoral gavage study (daily dosages of 20, 80, or 160 mg/kg) wasconducted in rats. Controls received the purified water vehicle.Treatment-related clinical signs were limited to postdosingsalivation. Increased relative liver weight (females, at 80and 160 mg/kg) was correlated with centrilobular hypertrophy,but was not associated with significant increased serum liverenzymes activities. These liver weight changes were interpretedas an adaptive metabolic response and were not considered toxicologicallysignificant. An increased incidence of centrilobular hepatocellularvacuolation representing lipid accumulation over that observedfor male controls occurred for males in all ipazilide-treatedgroups. This observation, however, was not correlated with elevatedhepatic enzyme activities. Hepatocellular basophilic foci wereobserved for females only (80 and 160 mg/kg groups); however,the significance of this lesion is unclear. Transient dosage-relatedduodenal villous atrophy/sloughing was observed for males fromthe 80 and 160 mg/kg groups. Mild increases in hemoglobin, hematocrit,urea, and creatinine (160 mg/kg), attributed to treatment, wereconsidered of minor toxicologic importance. Likewise, no clinicalor anatomical pathologic observations that may indicate cardiactoxicity were determined. It is concluded that a dosage of 20mg/kg (two to three times the clinical efficacious dosage) wasconsidered a no-effect dosage level since it did not produceany effects of toxicological significance.     

Kinetics of Drug Action in Disease States. XXXIX. Effect of Orally Administered Activated Charcoal on the Hypnotic Activity of Phenobarbital and the Neurotoxicity of Theophylline Administered Intravenously to Rats with Renal Failure

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure.     

Developmental Toxicity Evaluation of Isopropanol by Gavage in Rats and Rabbits

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosedorally with aqueous isopropanol (IPA; CAS No. 67–63–0)solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on GestationalDays (GD) 6 through 15 at a dosing volume of 5 mI/kg. Artificiallyinseminated New Zealand white rabbits, 15/group, were dosedorally with IPA at 0, 120, 240, or 480 mg/kg/day once dailyon GD 6 through 18 at 2 mI/kg. Maternal body weights, clinicalobservations, and food consumption were re corded throughoutgestation for both species. At scheduled euthanization for bothspecies (GD 20, rats; GD 30, rabbits), fetuses were weighed,sexed, and examined for external, visceral (including craniofacial)and skeletal alterations. For both species, the pregnancy ratewas high and equivalent across all groups; no dams or does aborted,delivered early, or were re moved from study. In rats, two dams(8%) died at 1200 mg/kg/ day and one dam (4%) died at 800 mg/kg/day.Maternal body weights and weight gain were equivalent acrossall groups, ex cept for statistically significantly reducedgestational weight gain (GD 0–20; 89.9% of control value),associated with statisti cally significantly reduced graviduterine weight at 1200 mg/kg/ day (89.2% of control value).There were no treatment-related clinical signs or effects onmaternal food consumption. All gestational parameters evaluatedwere equivalent across groups, including pre- and postimplantationloss, fetal sex ratios, and lit ter size. Twenty-two to 25 litterswere examined per group. Fe tal body weights per litter werestatistically significantly reduced at the two highest doses(97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for allfetuses and males and females separately). No evidence of increasedteratogenicity was observed at any dose tested in rats. In rabbits,four does (26.7%) died at 480 mglkg/day. Maternal body weightswere statistically significantly re duced during treatment (GD6–18) at 480 mg/kg/day (45.4% of control value) with anonsignificant reduction in gestational weight change (GD 0–30;77.3% of control value) at this dose. Profound clinical signsof toxicity and statistically significantly reduced maternalfood consumption were observed at 480 mgI kg/day. All gestationalparameters were equivalent across all doses administered. Thirteento 15 litters were evaluated per group except for the 480 mg/kg/daygroup with 11 litters (due to maternal deaths). There were notreatment-related effects on pre- or postimplantation loss,fetal sex ratio, litter size, or fetal body weight/litter. Moreover,no evidence was found of in creased teratogenicity at any dosetested in rabbits. Therefore, IPA was not teratogenic to CDrats or to NZW rabbits. The NOAELS for both maternal and developmentaltoxicity were 400 mg/kg/day in rats, and were 240 and 480mg/kg/day,respectively, in rabbits.     

Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg^-1 hr^-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β-phase (V_dβ) were within the range 0.394–0.616 1 kg^-1 with a mean value of 0.484 1 kg^-1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr^-1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.     

Analysis of the Complicated Nonlinear Pharmacokinetics of Orally Administered Telmisartan in Rats Using a Stable Isotope-IV Method

This study aimed to kinetically analyze the nonlinear absorption and systemic exposure of telmisartan (TEL) after oral administration to rats by using a stable isotope-IV method. Rats were orally administered different dose of TEL, followed by the intravenous injection of 0.005 mg/kg of deuterium-labeled TEL (TEL-d3). Assuming that TEL-d3 shows same pharmacokinetic properties with TEL, systemic clearance (CL_tot), oral bioavailability (F_oral), and intestinal and hepatic availability (F_a*F_g, F_h) of TEL were calculated in each individual rat. AUC_po of TEL increased disproportionately with dose and showed a sigmoid-type relation, indicating the involvement of multi-nonlinear processes in oral absorption of TEL. F_a*F_g of TEL increased with dose at the low-dose range while decreased at the high-dose range. In contrast, F_h increased and CL_tot decreased significantly in the middle range (2 to 6 mg/kg). As main factors of nonlinearity, saturations of solubility, efflux transport in the intestine, and the hepatic uptake of TEL were indicated. In conclusion, this study demonstrated a high possibility of a stable isotope-IV method to characterize complicated pharmacokinetic properties of oral drugs in animals, which can help to consider the future risks in their clinical use.     

Catabolism of Orally Administered l4C-Histamine in Man

Abstract: In previously published studies only 33–66% of the radioactivity was recovered in the urine after oral administration of ¹⁴C-histamine. In the present study the corresponding figures were higher: between 68 and 80% of the administered ¹⁴C-activity was recovered in the urine within the first 48 hours of administration. Between 1.8 and 18% was exhaled as ¹⁴CO₂, whereas between 13 and 19% of the administered radioactivity was excreted in the faeces. Thus nearly 100% of the administered ¹⁴C-activity was recovered. Urinary ¹⁴C-metabolites of histamine were determined by isotope dilution technique and by autoradiography. We were unable to obtain a constant specific activity for 1.4-methylimidazole-acetic acid by isotope dilution technique and an estimate of the balance between the urinary metabolites could not be obtained by this technique. Autoradiography indicated that oxidative deamination is the main pathway of orally administered histamine, and that imidazoleacetic acid riboside is the main urinary metabolite.