Acute target organ toxicity of 1-nitronaphthalene in the rat

1-Nitronaphthalene (1-NN) produced respiratory distress and centrilobular liver necrosis in male Sprague-Dawley rats after a single intraperitoneal injection (100 mg kg-1). Microscopic examination of the lungs of rats killed 24 h after the injection revealed a highly selective non-ciliated bronchiolar (Clara) cell necrosis as the only remarkable lesion. Pretreatment of animals with phenobarbital offered complete protection from the respiratory distress induced by 1-NN, but increased the severity of the hepatotoxicity. Pretreatment with SKF-525A protected against 1-NN-induced liver necrosis, but did not alter the incidence or severity of the respiratory distress. Under similar conditions, this pattern of toxicity was not seen with the structural analogue 2-nitronaphthalene.     

Lithium and the developing rat kidney in transplacental target organ toxicity

Pregnant female albino rats were treated orally with lithium carbonate dissolved in distilled water. Treatment at 100 mg/kg day 16 until day 20 of gestation caused marked maternal toxicity including polyuria. For the progeny increased rates of prenatal and postnatal mortality were noted. In part of the progeny sacrificed near term by Caesarean section, the visceral examination of the fetuses revealed an enlargement of the renal pelves in association with rudimentary or missing papillae. The renal anomalies are interpreted as being consistent with a developmental retardation due to specific lithium activity. After birth, i.e. after termination of maternal treatment, slight to moderate structural changes of the kidney were apparently compensated. 60 mg/kg through days 16-20 of pregnancy caused moderate maternal toxicity including polyuria. The offspring showed a postnatal development near the normal range, however, and no renal anomalies were recorded. In the view of the nephrotrophic property of lithium as known for the adult rat, the results indicate that possible transplacental effects on the fetal kidney as a target organ should be also considered.     

Oral and intravenous trichloroethylene pharmacokinetics in the rat

The pharmacokinetics of trichloroethylene (TCE) was studied in male Sprague-Dawley rats (300-350 g). TCE was administered intravenously and orally at doses of 5, 10, and 25 mg/kg to nonfasted rats and orally at 10 mg/kg to rats fasted for 8-10 h. The disappearance of TCE from the blood of intravenously dosed animals was best described by a two-compartment open pharmacokinetic model. The volume of the central compartment (Vc) approximated the rats' blood volume (50-70 ml/kg). The volume distribution (V beta) and total body clearance (CLT) decreased with increase in dose. The terminal half-life (t1/2) was about 120 min and was not affected by increases in dose. TCE was rapidly absorbed after oral dosing, with blood concentrations peaking between 6 and 10 min. The oral to intravenous bioavailability of TCE was 60-80% in nonfasted animals. The terminal t1/2 in fasted, orally dosed rats was identical to that when fasted rats were given the same dose intravenously. In fasted rats, bioavailability of an oral dose was greater than 90%, and peak levels in the blood were 2-3 times as high as in nonfasted rats.     

Species and strain differences in target organ alkylation and toxicity by 4-ipomeanol. Predictive value of covalent binding in studies of target organ toxicities by reactive metabolites.

The organ specificities of the in vivo covalent binding of 4-ipomeanol were closely correlated with the patterns of organ-specific damage by 4-ipomeanol in several different animal species and strains. In all species tested, the lung was a major target for 4-ipomeanol covalent binding and toxicity. In the hamster and the mouse, 4-ipomeanol caused liver necrosis and kidney necrosis, respectively, in addition to pulmonary damage. Correspondingly, high levels of covalent binding of 4-ipomeanol occurred in these target organs in these species. These in vivo results, in addition to studies of the in vitro covalent binding of 4-ipomeanol in microsome preparations from the various target tissues, were consistent with the view that the organ-specific toxicities of 4-ipomeanol were caused by a highly reactive 4-ipomeanol metabolite(s) primarily produced in situ in the respective target tissues. The present results suggest that studies of both the in vivo and the in vitro covalent binding of 4-ipomeanol may have some utility in predicting the target organ specificity of 4-ipomeanol toxicity in other species. The present investigations also have identified some relevant new in vivo toxicity models for future studies of the relationships between the metabolism and the toxicity of 4-ipomeanol.     

Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats

The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential toxicity of trans-permethrin in rainbow trout and mice: II. Role of target organ sensitivity

Previous studies demonstrated that even when trans-permethrin ester hydrolysis was inhibited in mice and the toxicity of trans-permethrin was increased at least 1.6 times by tri-o-tolyl phosphate (TOTP), the toxicity of trans-permethrin remained 60 times greater in the rainbow trout than in the mouse. This information suggested that factors other than metabolism, such as target organ sensitivity, may play a role in the differential toxicity of trans-permethrin between rainbow trout and mice. Since the brain of both the fish and the mouse is believed to be a site of action of the pyrethroids, the concentration of permethrin in the brains of these two species at the onset of signs of pyrethroid toxicity was measured in an attempt to establish a correlation between permethrin brain levels and toxicity in the fish and mammal. Signs of pyrethroid toxicity, such as intense whole body twitches and loss of equilibrium, were observed in rainbow trout when ¹⁴C-trans-permethrin brain levels exceeded 1.5 μg/g brain, regardless of whether the compound was administered iv or ip. Pyrethroid toxicity signs, such as intense tremors and loss of righting, were not observed in mice until ¹⁴C-trans-permethrin levels reached 25 to 30 μg/g brain. Thin-layer chromatographic analysis indicated that 85 to 95% of the ¹⁴C was parent compound in the rainbow trout brains compared to 60 to 70% in the mouse brains. ¹⁴C-cis-Permethrin produced lethality in trout and mice when the ¹⁴C-cis-permethrin brain concentrations were 2 and 6 μg/g, respectively. The results suggest that the rainbow trout may be physiologically more sensitive to the action of permethrin than is the mouse. In the trout, the cis and trans isomers appear to be equal in toxicity while in the mouse the cis isomer is more active than the trans isomer. The difference in isomer sensitivity between the trout and mouse may suggest differences in specificities at the site of pyrethroid action. The physiologic basis for this difference in pyrethroid toxicity is not understood.     

Paracetamol and metabolite pharmacokinetics in infants

BACKGROUND: Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (<6 weeks) or children (3-9 years). There are no studies investigating infants. METHODS: Infants ( n=47) undergoing major craniofacial surgery were given paracetamol 19-45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33-59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models. RESULTS: Mean (+/-SD) age and weight of the patients were 11.8+/-2.5 months and 9.1+/-1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric "1/4 power" models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance. CONCLUSION: Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.     

Pulmonary toxicity of trichloroethylene in mice. Covalent binding and morphological manifestations

We examined the time course of trichloroethylene (TCE)-induced pulmonary injury and focused on morphological changes and covalent binding of [14C]TCE soon after administration of a single dose of TCE (2000 mg/kg) to CD-1 male mice. At 1 hr after chemical treatment, Clara cells of the bronchiolar epithelium exhibited necrotic changes involving the mitochondria and endoplasmic reticulum. Dilatation of the endoplasmic reticulum became more severe at 2 hr after TCE administration and, by 4 hr, distended cisternae coalesced to form small vacuoles within the cytoplasmic matrix of the Clara cell. The severity of cellular damage increased progressively between 8 and 12 hr and, by 24 hr, the majority of Clara cells within an airway were severely vacuolated. Covalent binding of [14C]TCE to lung macromolecules was evident at 1 hr, peaked at 4 hr, declined thereafter, and reached a plateau between 12 and 24 hr. Peak binding (142.6 +/- 31.8 nmol/g of wet weight) represented approximately 20% of [14C]TCE distributed to the lung. Although the levels of binding in the liver were at all times greater than those in the lung, liver injury was relatively insignificant. The results demonstrate a positive correlation between the onset of Clara cell injury and the formation of reactive metabolites, as assessed by covalent binding of [14C]TCE.     

Metabolism and toxicity of trichloroethylene in epididymis and testis

The widespread occupational exposure to trichloroethylene (TCE) led us to test the hypothesis that TCE causes toxicity in the male reproductive system. We also investigated mechanisms mediating the potential cytotoxic response. Mice were exposed to TCE (1000 ppm) by inhalation for 6 h/day for 5 days/week for a total of 19 days. Exposure after the first week was interspersed by a "weekend." To estimate internal exposure, we measured the TCE metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCOH), in urine at Days 4, 9, 14, and 19. Urinary excretion of TCOH was significantly higher than TCA; levels of TCOH and TCA significantly increased by the second and third week, respectively. Cytochrome P450 2E1 (CYP2E1), an enzyme involved in TCE metabolism, was localized in the epididymal epithelium and testicular Leydig cells, and was found at higher levels in the former than the latter. Immunoblotting confirmed that CYP2E1 protein was present in greater amounts in epididymis than in testis. p-Nitrophenol hydroxylation, a CYP2E1 catalytic activity, was also higher in the epididymis than in the testis. Chloral, a major TCE metabolite, was generated in microsomal incubations at significantly higher levels in epididymis than in testis. Antibody inhibition of CYP2E1 reduced chloral formation, which was more pronounced in epididymis than in testis. After 4 weeks of TCE exposure, damage to the epididymis was manifested as sloughing of epithelial cells. These results indicated that TCE is metabolized in the male reproductive tract, leading to adverse effects that are more severe in the epididymis than in the testis.     

The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats

Male B6C3F1 mice metabolized inhaled trichloroethylene (TRI) (600 ppm/6 hr) to a greater extent (262% more) than male Osborne-Mendel rats. Mice metabolized more (332%) inhaled TRI to a hepatic macromolecular binding metabolite in vivo than rats. Oral administration of TRI resulted in treatment-related hepatocellular cytotoxicity in repeated dosing trials in the mouse. Hepatic effects observed in mice treated with a maximum tolerated dose of 2400 mg/kg/day TRI for 3 days were primarily centrilobular hepatocellular swelling with focal hepatocellular necrosis. These effects lead to an enhanced regenerative process as indicated by increased hepatic DNA synthesis activity (220% of control) and incidence of mitotic figures. Treatment of mice (po) with TRI for a 3-week period (5 days/week) resulted in a dose-related increase in hepatocellular swelling with giant and mineralized cells present in the 2400 mg/kg/day dosed animals. Contrasting the mouse data, rats appeared to be less sensitive to a maximum tolerated dose level of TRI, displaying enhanced hepatic DNA synthesis levels (175% of control) but no histopathology after a similar 3-week treatment with 1100 mg/kg/day TRI. Renal tissue in both species was not significantly affected by TRI. An estimate of the extent of TRI interaction with DNA was also determined by measuring the radioactivity associated with purified hepatic DNA. Only a very low level of in vivo TRI-DNA interaction was observed in mice given 1200 mg/kg TRI po which is reportedly tumorigenic upon chronic administration (maximum estimate = 0.62 ± 0.43 alkylation/10⁶ nucleotides). When coupled with the very weak or negative responses of pure TRI in in vitro mutagenesis assays, the DNA alkylation data indicate a lack of genotoxic potential. These data in toto suggest an epigenetic mechanism of tumor formation in the B6C3F1 mouse, implying that a tumorigenic response to TRI exposure in these animals would only be evident upon chronic administration of high, cytotoxic dose levels of TRI.     

Increased formic acid excretion and the development of kidney toxicity in rats following chronic dosing with trichloroethanol,a major metabolite of trichloroethylene

The chronic toxicity of trichloroethanol, a major metabolite of trichloroethylene, has been assessed in male Fischer rats (60 per group) given trichloroethanol in drinking water at concentrations of 0, 0.5 and 1.0 g/l for 52 weeks. The rats excreted large amounts of formic acid in urine reaching a maximum after 12 weeks ( approximately 65 mg/24 h at 1 g/l) and thereafter declining to reach an apparent steady state at 40 weeks (15-20 mg/24 h). Urine from treated rats was more acidic throughout the study and urinary methylmalonic acid and plasma N-methyltetrahydrofolate concentrations were increased, indicating an acidosis, vitamin B12 deficiency and impaired folate metabolism, respectively. The rats treated with trichloroethanol developed kidney damage over the duration of the study which was characterised by increased urinary NAG activity, protein excretion (from 4 weeks), increased basophilia, protein accumulation and tubular damage (from 12 to 40 weeks), increased cell replication (at week 28) and evidence in some rats of focal proliferation of abnormal tubules at 52 weeks. It was concluded that trichloroethanol, the major metabolite of trichloroethylene, induced nephrotoxicity in rats as a result of formic acid excretion and acidosis.     

Metabolism, toxicity, and carcinogenicity of trichloroethylene

Lifetime cancer or unit risk estimates for TRI have been calculated by the EPA on the basis of metabolized dose-tumor incidence relationships. Previously, it was common practice to directly extrapolate exposure dose-tumor incidence data from laboratory animal studies to predict cancer risks in humans. Such direct species-to-species extrapolations, however, do not take into account potentially important species differences in systemic uptake, tissue distribution, metabolism, deposition at the site(s) of action, and elimination. The consideration and use of pharmacokinetic and metabolic data can significantly reduce, though not eliminate, uncertainties inherent in species-to-species, route-to-route, and high- to low-dose extrapolations. The total amount of TRI metabolized was considered in the most recent EPA Health Assessment Document for Trichloroethylene to be the effective dose (EFD) producing tumors. Exposure dose-metabolism relationships were determined from direct measurement data in inhalation and oral dosing studies in mice and rats. The magnitude of TRI metabolism in these two species closely approximated body surface area. Thus, it was assumed that the amount of TRI metabolized per square meter of surface area was equivalent among species when calculating human equivalent doses from the animal data. Direct measurement data from an inhalation study in humans were used to calculate the amount of TRI metabolized and the unit risk estimate when a person inhales 1 microgram TRI per cubic meter continuously for 24 h. The EPA Cancer Assessment Group (CAG) elected to use this risk estimate for TRI in air, since it was calculated on the basis of a human metabolized dose rather than unit risk estimates based on animal studies. The current survey of literature and ongoing research uncovered no new animal or human studies in which TRI metabolites were directly measured, which would be any more suitable for use in estimating the total metabolized dose of TRI. On the basis of information now available, it is appropriate to continue to use the total amount of TRI metabolized as the EFD producing tumors in the liver. Use of the total amount metabolized represents an important "step in the right direction" in reducing uncertainties in interspecies extrapolations of data on a chemical such as TRI. TRI is believed to be metabolically activated to a reactive intermediate(s), although the identity of the intermediate(s) is unclear. There is evidence that formation of reactive intermediate(s) and TRI hepatotoxicity are directly proportional to the overall extent of TRI metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)     

Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits.

The extent to which interactions between enantiomers of disopyramide and between disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND), contribute to stereoselectivity of the anti-arrhythmic effect has been investigated in rabbits by measuring the prolongation of the QUc interval. The plasma unbound fraction of disopyramide enantiomers was constant at a concentration range of 1.44-28.9 microM. An intravenous infusion study of the disopyramide enantiomer or racemate suggested that the S-enantiomer had a pharmacological effect, determined by linear regression analysis, approximately 3.3-times more potent than that of the R-enantiomer. Furthermore, the effect caused by racemic disopyramide was the sum of that elicited by both enantiomers individually. No significant difference was observed between the slope of linear regression analysis of intravenous infusion and that of intravenous bolus injection. Single intravenous bolus injection of MND did not affect the QUc intervals. In conclusion, the S-enantiomer of disopyramide was approximately 3.3-times more potent pharmacologically than the R-enantiomer. The relationship between plasma concentration of the disopyramide enantiomers and pharmacological effect was the sum of each enantiomer individually.     

Zidovudine pharmacokinetics in zidovudine-induced bone marrow toxicity.

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.     

Differentiated cell and organ culture in toxicity testing.

Abstract The safety evaluation of new chemicals involves a range of investigations, including acute and sub-acute toxicity testing, long-term toxicity testing, studies on mutagenicity, carcinogenicity, and reproductive toxicity, and special investigations involving the interaction of the chemical under test with particular parts of the body, such as the skin or the nervous system. We shall consider the potential role of differentiated cell and organ culture in toxicity testing, and the criteria available for assessing cell viability, damage, and death, with a view to establishing whether such methods could be used for determining the relative acute toxicities of chemicals. We shall also consider methods for studying the effects of chemicals on general and specific aspects of cell structure and function, including liver cell and organ cultures both as primary targets themselves susceptible to damage and as providers of metabolically activated compounds able to affect other cells and tissues.     

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans.

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate (MPH) and its major metabolite, dl-ritalinic acid (RA), were examined in a cohort of healthy subjects. On two occasions, separated by one week, each subject received MPH.HCl either intravenously (10 mg) or orally (40 mg). Urine was collected in six time segments, up to 16 h after each dosing. In the first 2 h after oral administration of MPH, d-MPH found in the urine was 10-fold greater than the l-antipode, whereas there was no significant difference between the amounts of MPH enantiomers excreted after the intravenous dose. Examination of RA content in the 0-2-h urine samples after oral administration of MPH indicated the presence of higher levels of l-RA (d-RA:l-RA, 0.37), whereas after intravenous MPH, there was no significant difference between the amounts of RA enantiomers. Moreover, after oral administration of MPH, the ratio of d-MPH to l-MPH was approximately 10 in urine samples from each of the time segments. By contrast, after intravenous administration of MPH, the d:l ratio changed progressively from 1.16 in the 0-2-h urine sample to 9.06 in the 12-16-h sample. These observations suggest that, after oral administration of dl-MPH, the distortion in the ratio of MPH or RA enantiomers in urine samples was attributable to enantioselective presystemic conversion of MPH to RA rather than to enantioselective excretion.     

临床前药物安全评价毒性病理学靶器官毒性的检查及评价

临床前药物安全评价毒性病理学靶器官毒性的检查和评价要结合大体病理学、组织病理学及临床病理学检查结果进行全面考虑、逐步分析,并使用国际统一推荐的诊断术语及诊断标准,避免主观、不确切的诊断。简要介绍了临床前药物安全评价毒性病理学靶器官毒性检查的基本原则,大体病理学检查,组织病理学检查,毒性病理学诊断方法、程序及注意事项,诊断术语及诊断标准的国际统一,临床病理学参数分析,解剖病理学与临床病理学数据结合一致性分析等内容,以期为我国临床前药物安全评价毒性病理学靶器官毒性检查及评价提供一定参考。     

Effect of lamotrigine on the pharmacokinetics of carbamazepine and its active metabolite in dogs.

The effect of lamotrigine (LTG) on the pharmacokinetics of carbamazepine (CBZ) and its active metabolite; carbamazepine-epoxine (CBZ-E), was investigated in dogs. Five male dogs received CBZ (2 x 200 mg tab, p.o.) daily for a period of 1 week. After the end of this period, blood samples were collected serially for up to 24 hrs. After a wash-out period of I week, LTG (100 mg tab, p.o.) was coadministered with the CBZ dose (2 x 200 mg tab, p.o.) for 7 days. Blood samples were again serially collected and plasma levels of CBZ and CBZ-E were analysed by high performance liquid chromatography (HPLC). Concurrent administration of LTG with CBZ did not have any significant effect on the pharmacokinetic parameters of CBZ. There was also no significant difference between the plasma concentration ratio (CBZ-E to CBZ) vs time profiles in the two schedules of drug administration signifying the absence of pharmacokinetic interaction between LTG and CBZ or its active metabolite in this animal model.     

Roles of exercise and pharmacokinetics in cerivastatin-induced skeletal muscle toxicity.

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are associated with adverse skeletal muscle effects, but the underlying mechanisms remain unclear. To determine whether toxicity involves the level of drug exposure in muscle tissue and to test the effect of exercise on cerivastatin (CVA)-induced skeletal muscle damage, female rats were administered vehicle or CVA at 0.1, 0.5, and 1.0 mg/kg/day by gavage for two weeks and exercised or not on treadmills for 20 min/day. Clinical chemistry and plasma and tissue pharmacokinetics were evaluated; light and transmission electron microscopy (TEM) of Type I and Type II fiber-predominant skeletal muscles were performed. Serum levels of AST, ALT, CK, and plasma lactic acid were significantly elevated dose-dependently. CVA treatment decreased psoas and quadriceps weights. At 1 mg/kg all muscles except soleus demonstrated degeneration. Exercise-exacerbated severity of CVA-induced degeneration was evident in all muscles sampled except soleus and quadriceps. Early mitochondrial involvement in toxicity is suggested by the numerous membranous whorls and degenerate mitochondria observed in muscles at 0.5 mg/kg. No significant differences in CVA concentrations between either EDL and soleus or plasma and muscle were found. We found that CVA had no effect on cleaved caspase 3. In summary, we found that treadmill exercise exacerbated the incidence and severity of CVA-induced damage in Type II fiber-predominant muscles. Tissue exposure is likely not the key factor mediating CVA-induced skeletal muscle toxicity.     

Dose-independent pharmacokinetics of trimethadione and its metabolite in rats

The aim of the present study was to examine the dose-independent kinetics of trimethadione (1) and its only metabolite dimethadione, 5,5-dimethyl-2,4-oxazolidinedione (2), after oral administration of 1-, 2-, and 4-mg/kg doses of 1 to rats. Pharmacokinetic parameters determined after oral administration of these doses showed that the half-life (t 1/2), metabolic clearance (CL), and apparent volume of distribution (Vd) were not significantly changed by increasing or decreasing the dose of 1, whereas there was a linear relationship between the dose of 1 and the area under the curve (AUC) (1, r = 0.912; 2, r = 0.976) or the maximum serum concentration (Cmax) (1, r = 0.990; 2, r = 0.980). The ratios of 2 to 1 at 1 and 2 h after oral administration of 1 were not significantly different. These experiments indicate that serum pharmacokinetic behavior of 1 and 2 1 or 2 h after oral administration of 1 to the rat is independent of the dose of 1 in the 1-4 mg/kg range.