Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs

Recent reports indicate that bupropion, a novel non-tricyclic antidepressant, is metabolized differently in certain species of animals. To further define the disposition of bupropion, a study was done involving three species, the rat, mouse, and guinea pig, as animal models to evaluate bupropion metabolism. The pharmacokinetic profiles of bupropion and its major basic metabolites, BW 306U and BW A494U, were determined following the ip administration of 40 mg/kg bupropion to these animals. Pharmacokinetic profiles of the parent drug and metabolites from plasma and brain samples were obtained using a liquid chromatographic procedure. Further investigation of the reduced bupropion metabolite BW A494U was carried out by the ip administration of this metabolite to these animals and assaying the plasma and brain samples 90 min after dosing. Analysis of the pharmacokinetic data revealed that the rat quickly metabolized bupropion, but no basic metabolites accumulated. The mouse metabolized bupropion predominantly to BW 306U, whereas the guinea pig converted bupropion to reduced bupropion (BW A494U) as well as BW 306U. Brain/plasma ratios of bupropion among these animals did not vary significantly. However, both metabolites showed dramatic differences in their brain/plasma ratios among these species. When reduced bupropion (BW A494U) was injected, almost 3% of the plasma concentration of BW A494U was determined to be bupropion in the rat. Lesser amounts were converted in the mouse and guinea pig. Therefore, we have demonstrated that distinct differences exist in the metabolism of bupropion in various species of animals. The guinea pig, when compared to the rat or mouse, appears to constitute a model that most closely resembles that of human bupropion metabolism.     

Stability of bupropion and its major metabolites in human plasma

Bupropion (BUP) is a new, monocyclic, second-generation antidepressant with efficacy comparable with that of the tricyclics but possessing a more favorable side-effect profile. Therapeutic drug monitoring services are expected to be widely available following the marketing of BUP, yet relatively little has been published on its clinical pharmacokinetics. The purpose of this study was to assess the drug's plasma stability and to determine the best storage conditions for conducting pharmacokinetic studies of BUP and its major metabolites. Human plasma was spiked with known concentrations of BUP and its major basic metabolites, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB), and incubated under varying conditions of temperature and pH. BUP showed a log linear degradation that was both temperature and pH dependent. BUP half-life in pH 7.4 plasma stored at 22 and 37 degrees C was 54.2 and 11.4 h, respectively. Incubation at 37 degrees C, pH 2.5 to 10, for 48 h had minimal effect on metabolite concentrations. These results indicate that drug degradation must be considered in studies involving the incubation of plasma for protein binding determinations and the collection and storage of plasma samples for drug concentration analysis during therapeutic drug monitoring.     

Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs

Thiamphenicol is an analogue of chloramphenicol and is characterised by a broad spectrum of action. In this study, serum and lung levels of thiamphenicol (TAP) were studied in infected guinea pigs after the administration of thiamphenicol glycinate N-acetylcysteinate (TGA). Animals received a single dose of TGA (15 mg/kg, subcutaneously) immediately after intra-tracheal infection with Haemophilus influenzae (about 10⁷ CFU/animal). Serum and lung concentrations of TAP were determined at 0, 1, 3, 6, 12 and 24 h after drug administration by means of HPLC. TAP serum levels were elevated at 1 h and remained detectable for 24 h after drug administration. Tissue lung levels were comparable to peak serum concentrations but remained higher and decreased more slowly than serum concentrations.     

椎基底动脉缺血／再灌注对豚鼠听功能和耳蜗形态学影响

目的 探讨椎基底动脉缺血／再灌注耳蜗损伤后耳蜗病理形态学和听功能改变。方法经颅底径路建立豚鼠椎基底动脉缺血／再灌注耳蜗损伤模型。68只豚鼠随机分成6组：正常组、缺血1h组、缺血再灌注组（按再灌注时间分12h、24h、48h．7d,4组）。各组动物分别于手术前和处死前行听性脑干反应（auditory brainstem response,ABR）测定,观察ABR各波潜伏期、Ⅰ-Ⅲ波间期和Ⅲ波阈值,部分动物观察了缺血时ABR变化。耳蜗组织切片HE染色技术观察组织细胞形态变化。结果血管阻断缺血时ABR表现波形不典型,重复性差,在缺血10～20min后波形逐渐稳定;缺血组与再灌注（12h、24h、48h、7d）各组ABR各波潜伏期和Ⅰ-Ⅲ波间期较正常组延长,Ⅲ波阈值升高,尤以再灌注24h变化最为显著,48h和7d后ABR阈值有所恢复,但不能恢复正常。耳蜗病理形态学改变发现缺血组毛细胞变形肿胀,再灌注（12h、24h、48h．7d）各组损伤进一步加重,再灌注24—48h损伤最重,可见明显外毛细胞缺损,螺旋神经元胞体和神经纤维较正常组减少,血管纹变薄,均以基底转为明显。结论豚鼠椎基底动脉缺血／再灌注时可致耳蜗损伤,表现为听功能和耳蜗组织形态学改变。     

太子健对哮喘豚鼠白细胞介素-5 P-选择素的影响

目的　观察太子健 对反复诱发哮喘的哮喘豚鼠血中白细胞介素 (IL) - 5、黏附分子 P-选择素的影响。方法　将豚鼠随机分为正常组、模型组、地塞米松组、太子健 高剂量和低剂量组 5组 ,后 4组分别用卵蛋白致敏 15 d后 ,再用卵蛋白反复诱发哮喘 ,正常组用生理盐水代替 ,同时 ,正常组和模型组灌服生理盐水 ,其余 3组分别灌服地塞米松、高剂量和低剂量太子健 ,予以治疗 ,连续 15 d。结果　太子健 可减少血中 IL- 5、黏附分子 P-选择素的含量。结论　太子健 可以影响 IL- 5、P-选择素对炎症细胞的调节作用 ,从而减轻气道慢性变应性炎症 ,具有一定的抗哮喘复发的作用。     

Effect of quinidine on the intestinal secretion of digoxin in guinea pigs

Following i.v. injection of digoxin (10 μg kg^?1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearily with time. After 3 h, L/P was 8·7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg^?1 p.o., 2h before experiment) both the L/P ratio (5·7; p < 0·01) and the digoxin content of jejunal tissue (– 32 per cent; p < 0·01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.     

Effect of arsenic on carbohydrate metabolism after single or repeated injection in guinea pigs

Divergent pattern in pyruvate efflux from livers perfused with As₂O₃ and livers of animals previously repeatedly treated with the toxicant was observed in earlier experiments (Reichl et al. 1987, 1988). Further studies of the effect of As₂O₃ on carbohydrate metabolism were therefore performed. Male guinea pigs received either a single dose of As₂O₃ 10 mg· kg^–1 s.c. or repeated doses of 2.5 mg·kg^–1 bis in die (b.i.d.) on 5 consecutive days. One hour after the single dose or 1 h and 16 h after the last injection in the repeated treatment group the animals were sacrificed under anaesthesia. The livers were removed by a freeze-stop technique and the contents of glycogen and glycolysis intermediates were measured. In the single dose group a decrease in fructose-1,6-diphosphate and glycerolaldehyde-3-phosphate and an increase in phosphoenolpyruvate and pyruvate was observed. In the repeat dose, 1-h group a significant decrease in glycogen, glucose-6-phosphate, fructose-6-phosphate, glycerolaldehyde-3-phosphate, dihydroxyacetonephosphate, 2-phosphoglycerate and pyruvate was found. In the repeat dose, 16-h group the contents of glycogen, glucose-6-phosphate, pyruvate and lactate were diminished. The most prominent finding after repeated As₂O₃ administration was a marked depletion in total carbohydrate content. This was due mainly to depletion of glycogen.     

The differential effect of lithium on noradrenaline- and dopamine-sensitive accumulation of cyclic AMP in guinea pig brain

Lithium (Li) in its narrow therapeutic concentration range was found to inhibit only the noradrenaline- and not the dopamine-sensitive accumulation of cyclic AMP in guinea pig brain. The results suggest a pharmacological distinction between the antischizophrenic drugs that inhibit dopamine-sensitive cyclic AMP accumulation and Li, an antimanic agent that inhibits specifically only the noradrenalinesensitive cyclic AMP accumulation.     

The effect of bupropion on nicotine craving and withdrawal

Rationale and objectives: Bupropion has demonstrated efficacy for smoking cessation. Given the importance of nicotine craving and withdrawal in the smoking cessation process, the current study examined the effects of bupropion on these parameters during smoking abstinence. Methods: During a 2-day Baseline phase with ad lib smoking, 91 non-depressed smokers (who were not trying to quit permanently) were administered measures of nicotine craving, withdrawal symptoms, and timed measures of cognitive performance five times daily. Participants were then assigned randomly to a 14-day treatment regimen with bupropion 300 mg/day, bupropion 150 mg/day, or placebo. Thereafter, the above measures were re-administered during 3 days of abstinence on a closed research ward. Results: Relative to placebo, 300 mg bupropion significantly reduced abstinence-associated increases in rated depression, difficulty concentrating, and irritability, and attenuated a decrease in positive affect. The results also suggested that bupropion might have a positive effect on performance measures during the withdrawal period. No effects were observed on craving, anxiety, restlessness, or hunger. The lack of findings on craving measures may be explained by a floor effect; except on the first day of abstinence, neither drug nor placebo groups showed much craving elevation during abstinence. Conclusions: Study results indicate that bupropion ameliorates some nicotine withdrawal symptoms. Received: 24 February 1999 / Final version: 15 August 1999     

Serum and lung levels of thiamphenicol after administration of its glycinate N-acetylcysteinate ester in experimentally infected guinea pigs

Thiamphenicol is an analogue of chloramphenicol and is characterised by a broad spectrum of action. In this study, serum and lung levels of thiamphenicol (TAP) were studied in infected guinea pigs after the administration of thiamphenicol glycinate N-acetylcysteinate (TGA). Animals received a single dose of TGA (15 mg/kg, subcutaneously) immediately after intra-tracheal infection with Haemophilus influenzae (about 10⁷ CFU/animal). Serum and lung concentrations of TAP were determined at 0, 1, 3, 6, 12 and 24 h after drug administration by means of HPLC. TAP serum levels were elevated at 1 h and remained detectable for 24 h after drug administration. Tissue lung levels were comparable to peak serum concentrations but remained higher and decreased more slowly than serum concentrations.     

Pharmacokinetics of oral diltiazem and five of its metabolites in patients with chronic renal failure

The pharmacokinetics of oral diltiazem were studied in 10 patients with chronic renal failure not requiring dialysis and in five healthy volunteers after a single dose of 120 mg. We found that patients with chronic renal failure had lower amounts of unchanged diltiazem and of its main metabolite (MA) in urine and a trend to have slightly higher values of plasma concentration. Since the terminal elimination phase is not affected by chronic renal failure we conclude that this trend is probably the result of alterations in the volume of distribution of diltiazem in these patients.     

Effects on mitochondrial metabolism in livers of guinea pigs after a single or repeated injection of As2O3

Differences in the metabolite pattern were observed in previous experiments in guinea pig livers after a single injection or prolonged (5 days) treatment with AS₂O₃ (Reichl et al. 1988). To elucidate the underlying mechanism the effect of As₂O₃ on liver metabolism was therefore investigated. Male guinea pigs received either a single dose (s. d.) of As₂O₃ 10 mg × kg^–1 s. c. or repeated doses (r. d.) of 2.5 mg × kg^–1b. i. d. on 5 consecutive days. One hour after the s. d. or 1 h and 16 h after the last injection in the r. d. groups the animals were sacrificed in anaesthesia. The livers were removed by freeze clamping for the determination of various metabolites. In the s. d. group a significant decrease in hydroxybutyrate, acetylCoA, adenosinemonophosphate and in the ratio of hydroxybutyrate/acetoacetate and an increase in pyruvate, citrate, malate, and adenosinetriphosphate were observed. A significant decrease in glycogen, pyruvate, -ketoglutarate, acetylCoA, and acetoacetate and a significant increase in malate and in the ratios of lactate/pyruvate and hydroxybutyrate/acetoacetate were observed in the r. d.1-h group. In the r. d.16-h group a significant decrease in glycogen, pyruvate, lactate, and adenosinemonophosphate was found, but the values tended towards control values. The data are consistent with mechanisms of As₂O₃ toxicity in other species as PDH inhibition with consecutive citric acid cycle and gluconeogenesis inhibition and excessive carbohydrate depletion.     

班布特罗对豚鼠实验性哮喘的作用及其机理研究

目的 研究班布特罗对豚鼠实验性哮喘的作用、药效学及药动学特点及作用机制。方法 组胺和卵清蛋白诱发在体豚鼠实验性哮喘模型,使用豚鼠离体气管片和肺条进行研究。结果 班布特罗剂量依赖性抑制组胺和卵清蛋白诱发的豚鼠哮喘,班布特罗对豚鼠气管片无松弛作用,而灌服其后的松弛气管片和肺条血浆呈剂量依赖性,且对肺条的松弛作用强于气管片。其峰效应出现于给药后4h前后,作用持续24h以上。结论 班布特罗作为特布他林的前药对豚鼠实验性哮喘的作用缓和而持久。     

Study on the mechanism of photosensitive dermatitis caused by ketoprofen in the guinea pig

To investigate the mechanism on photosensitive dermatitis caused by ketoprofen (KP) in humans, the following experiments were performed by topical application on guinea pigs. The phototoxicity study involving treatment with 10% solution of KP, its enantiomers (R-KP and S-KP), loxoprofen, and flurbiprofen revealed no phototoxic reactions. In the photoallergenicity study, KP and its enantiomers (0.5–2% solution) induced skin reaction at all dosages; however, loxoprofen and flurbiprofen (1–5% solution) did not induce such a photoallergenic reaction. These results suggest that the chemical structure of the benzophenone chromophore in KP would be one of the important factors for induction of the photoallergy since both loxoprofen and flurbiprofen do not possess this structure and hence lack photoallergenic potential. Furthermore, to assess time profiles of KP concentration in the skin and plasma, guinea pigs received a repeated topical application of R-KP and S-KP at a dosage of 40 mg/kg over a period of 3 days. Plasma KP concentrations were extremely low as compared to skin KP concentrations and were not detected at 72 h after the final dosing. At 24 h after the final dosing, KP concentrations in the skin with R-KP and S-KP treatment were 187.4 and 254.7 μg/g, respectively, and their half-lives were 80.5 and 84.4 h, respectively. KP concentrations at 336 h after final dosing were 11.3 μg/g for R-KP and 15.7 μg/g for S-KP treatment. The acylglycerol-combined KP concentrations at 336 h were 2% or less as compared to KP concentrations with R-KP and S-KP treatment. There were no differences in KP concentrations in the skin between R-KP and S-KP and in combined KP concentrations between the enantiomers. The present study indicates that photosensitive dermatitis after topical application of KP in humans, caused by photoallergenicity and not phototoxicity, can be reproduced in the animal testing, and suggests that the skin reaction may be caused by the long period of retention of KP in the skin.     

Pharmacokinetics of acetylmethadols II: Plasma levels of D- and L-α-acetylmethadol and their major metabolites in the dog

The pharmacokinetics of the synthetic narcotic agent LAAM, its pharmacologically active, demethylated metabolites NORLAAM and DINORLAAM, and also the dextro-enantiomer DAAM, were examined following intravenous doses of all four compounds, and oral doses of LAAM and DAAM to dogs. Extensive tissue uptake of all compounds occurred following intravenous doses. NORLAAM penetrated into tissues to a greater extent than LAAM or DINORLAAM and also exhibited the longest biological half-life (11·7 h) in plasma compared to LAAM (6·5 h) and DINORLAAM (3·6 h). The elimination rate of DINORLAAM was prolonged following oral doses of LAAM and intravenous doses of NORLAAM, and it is suggested that prolonged pharmacologic activity of LAAM may be associated with rate-limiting demethylation of NORLAAM. DAAM was taken up exrensively by tissues but to a smaller extent than LAAM. Following oral doses, the bioavailability of LAAM as unchanged drug was 22·6 and 32·5 per cent in two dogs while that of DAAM was 4·9, 9·3, and 14·6 per cent in three dogs. Poor bioavailability of unchanged drug from oral doses appears to be due partly to first-pass metabolism and is partially compensated for by increased plasma levels of pharmacologically active metabolites. Extensive tissue uptake of LAAM and its active metabolites, and their long plasma half-lives, may be partially responsible for the prolonged pharmacologic activity of LAAM reported in patients maintained on this drug.     

The effect of adipose derived stromal cells on oxidative stress level,lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic disease and a major cause of death and disability. The present study aimed to elucidate pharmacological effects of adipose derived stromal cells (ASCs) on pathological and biochemical factors in a guinea pig model of COPD. Guinea pigs were randomized into 5 groups including: Control, COPD, COPD + intratracheal delivery of PBS as a vehicle (COPD-PBS), COPD + intratracheal delivery of ASCs (COPD-ITASC) and COPD + intravenous injection of ASCs (COPD-IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was performed immediately after the end of animal exposure to cigarette smoke and 14 days after that, white blood cells, oxidative stress indices and pathological changes of the lung were measured.

Results

Compared with control group, emphysema was clearly observed in the COPD and COPD-PBS groups (p < 0.001). Lung histopathologic changes of COPD-ITASC and COPD-IVASC groups showed non-significant improvement compared to COPD-PBS group. The COPD-ITASC group showed a significant increase in total WBC compared to COPD-PBS group but there was not a significant increase in this regard in COPD-IVASC group. The differential WBC showed no significant change in number of different types of leukocytes. The serum level of malondialdehyde (MDA) significantly decreased but thiol groups of broncho-alveolar lavage fluid (BALF) increased in both cell treated groups (p < 0.05 for all cases). Weight of animals decreased during smoke exposure and improved after PBS or cell therapy. However, no significant change was observed between the groups receiving PBS and the ones receiving ASCs.

Conclusion

Cell therapy with ASCs can help in reducing oxidative damage during smoking which may collectively hold promise in attenuation of the severity of COPD although the lung structural changes couldn’t be ameliorated with these pharmacological therapeutic methods.     

Pharmacokinetics of mirtazapine and its main metabolites after single intravenous and oral administrations in rats at two dose rates

Background

Mirtazapine (MRZ) is a human antidepressant drug metabolized to 8-OH mirtazapine (8-OH) and dimethylmirtazapine (DMR) metabolites. Recently, this drug has been proposed as a potential analgesic for use in a multidrug analgesic regime in the context of veterinary medicine. The aim of this study was to assess the pharmacokinetics of MRZ and its metabolites DMR and 8-OH in rats.

Findings

Eighteen fasted, healthy male rats were randomly divided into 3 groups (n = 6). Animals in these groups were respectively administered MRZ at 2 and 10 mg/kg orally and 2 mg/kg intravenously. Plasma MRZ and metabolite concentrations were evaluated by HPLC-FL detection method. After intravenous administration, MRZ was detected in all subjects, while DMR was only detected in three. 8-OH was not detected. After oral administration, MRZ was detected in 3 out of 6 rats treated with 2 mg/kg, it was detected in 6 out of 6 animals in the 10 mg/kg group. DMR was only detectable in the latter group, while 8-OH was not detected in either group. The oral bioavailability was about 7% in both groups.

Conclusions

The plasma concentration of the MRZ metabolite 8-OH was undetectable, and the oral bioavailability of the parental drug was very low.     

Radioassay of chlorpromazine and its metabolites in plasma

Conditions have been established for the quantitative formation of radiolabeled derivatives of chlorpromazine, chlorpromazine sulfoxide and their demethylated analogs in plasma extracts.Tritiated N-acetyl derivatives are formed from the demethylated compounds and C¹⁴-quaternary amines from the tertiary amines by acetylation and methylation, respectively. These reactions are quantitative over a wide range of concentrations.The reactions may be performed sequentially when chloropromazine and its Nor derivatives (or chlorpromazine sulfoxide and its Nor derivatives) exist in a single extract. Herein, the mixture is first acetylated and subsequently methylated. The labeled derivatives are quantitatively separated and recovered by selective solvent partition.An extraction procedure has been suggested by which chlorpromazine and its Nors may be separated from chlorpromazine sulfoxide and its Nor derivatives so that each fraction may be subjected to the sequential acetylation and methylation reactions. Recoveries of g quantities of standards from plasma are less than quantitative, probably because of losses due to glass adsorption and protein binding, but may be corrected with appropriate internal standards. As low as 15–20 ng/ml of each compound are measurable in a 3 ml plasma aliquot.The method has been applied to a limited number in vivo experiments in dogs and in humans.This investigation was supported under a Public Health Service contract (No. PH-43-65-68) to the New England Nuclear Corporation, Biomedical Assay Laboratories, Boston, Massachusetts.New England Nuclear Corporation, Biomedical Assay Laboratories.     

The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers

The effect of food on the pharmacokinetics of the antiepileptic oxcarbazepine (OXC) was investigated in healthy volunteers. Six healthy male volunteers were treated with single peroral doses of 600 mg of oxcarbazepine (Trileptal®) after overnight fasting or a fat- and protein-rich breakfast. Mean (± SD) areas under the plasma concentration—time curves (AUC) of the major component in plasma, the active monohydroxy metabolite (MHD), which is responsible for the therapeutic effect in man, were 672 (25) μmol L^?1 h when given to the fasted volunteers and 780 (31) μmol L^?1 h (p = 0.042) when given after a substantial breakfast. Mean (± SD) maximum concentrations (C_max) were 25.5 (4.8) μmol L^?1 when given to the fasted volunteers and 31.4 (5.3) μmol L^?1 (p = 0.025) when given after breakfast. Thus, the average AUC was increased by 16% and C_max by 23% when oxcarbazepine was given with food. The times at which C_max was reached (t_max) as well as the terminal half-lives were not influenced by concomitant intake of food. The tolerability was the same whether oxcarbazepine was given before or after food in healthy volunteers. The slight effect of food on the kinetics of oxcarbazepine should be of little therapeutic consequence.     

Effect of undecylenic acid as a topical microbicide against genital herpes infection in mice and guinea pigs

There is increasing interest in the use of topical microbicides to help prevent the spread of sexually transmitted diseases (STD). Undecylenic acid (UA), a monosaturated fatty acid, is the active ingredient in a number of over-the-counter (OTC) antifungal spray powders, that also exhibits in vitro antibacterial and antiviral activity, including herpes simplex virus (HSV) activity. We, therefore, evaluated UA as a topical microbicide against genital HSV infection using the murine and guinea pig models of genital herpes. Mice were administered a 20% solution of UA in polyethylene glycol (PEG) vehicle, vehicle alone or phosphate buffered saline (PBS) intravaginally immediately prior to vaginal challenge with HSV-2. Pre-treatment with UA decreased the number of mice that became infected (P<0.001 vs. PBS or vehicle control), developed symptoms (P<0.001) or died (P<0.001). However, when treatment was extended to either 5 min prior to or after viral inoculation, protection was lost. Similar findings were found using the guinea pig model, where UA treatment completely prevented HSV-2 vaginal infection when given immediately prior to HSV-2 inoculation (P<0.001 vs. PBS or vehicle control). Thus, UA, an approved OTC medication, provided significant protection against HSV disease and infection only when applied immediately before viral inoculation, indicating that better formulations were needed to extend the duration of protection.