Structural identification of bitespiramycin metabolites in rat: A single oral dose study

Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSⁿ method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80?mg?kg^?1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4′′-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.     

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium

Summary The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC.The mean C_max of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg.With 4-AA, the increase in mean C_max was linear, but the increase in AUC was not.The increases in mean C_max and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose.The increases in mean C_max and AUC for 4-AcAA were roughly proportional to the increase in dose.There were no significant differences in renal clearance between doses for any of the four metabolites.The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.     

Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects

The 3-day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4±2.0 per cent (mean ± S.E.M.) of the dose. By HPLC 424 ± 2.7 per cent was recovered before and 44.0 ± 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 ± 2.9 per cent; of this 0.7 ± 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 ± 0.3 per cent before and 3.4± 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4.8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.     

大鼠一次性灌服酸枣仁提取物后棘苷的药代动力学研究

目的用反相高效液相色谱法,以磺胺甲唑为内标,对一次性ig酸枣仁提取物后的大鼠血浆中棘苷进行药代动力学研究。方法血浆样品经乙腈沉淀蛋白后,于50 ℃氮气流下吹干,残渣用流动相溶解后进行分析。色谱条件为色谱柱:Hypersil C₁₈柱,200 mm×4.6 mm ID,5 μm;流动相:乙腈-水-冰醋酸(15∶85∶1);流速:0.7 mL·min^-1;检测波长:334 nm;柱温:35 ℃。结果血浆中棘苷在18.1～903.5 μg·L^-1成良好线性关系(R²≥0.995)。平均回收率为94.5%,日内、日间精密度RSD均小于9.0%。该法定量限为18.1 μg·L^-1,血浆样品在-20 ℃可稳定保存。结论该法简便、灵敏、准确,可用于大鼠一次性灌服酸枣仁提取物后血浆中棘苷的浓度测定及其药代动力学研究。     

Effect of a single oral dose of ddt on lipid metabolism in rat

A single oral dose of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT) (600 $\text{mg}\text{kg}$ body weight) was given to rats and the levels of various lipids in adipose tissue, liver and plasma were studied. No alteration was observed in the levels of various lipid classes in these tissues except for a decrease in the phospholipid and triglyceride fractions of liver. Lipoprotein lipase activity of post-heparin plasma (protamine-sensitive and -resistant) was significantly decreased, whereas in liver and adipose tissue, the activity of this enzyme remained unchanged.     

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone

Objective: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. Methods: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. Results: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5–2 h) and 0.83 (for samples taken between 4–12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. Conclusion: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone. Received: 3 December 1997 / Accepted in revised form: 3 June 1998     

Pharmacokinetics of chloroquine and some of its metabolites in healthy volunteers: a single dose study

Eight healthy volunteers who had not taken chloroquine 2 to 12 months previously participated in a single dose study designed to evaluate the pharmacokinetics of chloroquine and some of its metabolites. Each subject received two tablets of chloroquine sulfate (300 mg base) only. Blood and urine samples were collected just before and periodically after chloroquine administration. These samples were assayed for chloroquine and its N-dealkylated metabolites (monodesethylchloroquine, didesethylchloroquine, 7-chloro-4-aminoquinoline), chloroquine side chain N-oxide and chloroquine di-N-oxide using a high performance liquid chromatographic method. Residual levels of chloroquine and its N-oxidation metabolites were found in all subjects. 7-chloro-4-aminoquinoline was eliminated more slowly (t1/2z = 126.48 +/- 20.13 h) than the other metabolites and the unchanged drug (t1/2z = 106.43 +/- 10.13 h). Also, 7-chloro-4-aminoquinoline had a significantly faster (Student's t-test, P less than 0.05) formation clearance when compared with the other metabolites. The plasma concentration of 7-chloro-4-aminoquinoline was about twice that of the unchanged drug while the plasma concentration of monodesethylchloroquine was about 46% that of the unchanged drug. In order to investigate whether the metabolites were produced from the same binding sites or closely related sites on the cytochrome P-450 system, their formation clearances were correlated. The best correlation (r2 = 0.83) was observed for didesethylchloroquine and monodesethylchloroquine, and a fair correlation (r2 = 0.59) was observed for monodesethylchloroquine and 7-chloro-4-aminoquinoline. Formation clearances of the other metabolites were poorly correlated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Albendazole and its metabolites in the breast milk of lactating women following a single oral dose of albendazole

AIMS

Albendazole (ABZ) is used in several anthelminthic drug programmws. ABZ side-effects are generally mild, but ABZ-induced pancytopenia may be serious. In filariasis programmes, it may be necessary to administer ABZ to breastfeeding women. Few data are available on safety of ABZ for breastfed infants. In addition, the pharmacokinetics of ABZ and its metabolites in human milk is insufficiently investigated. The aim was to study pharmacokinetics of ABZ and its metabolites [ABZ sulphoxide (ABSX) and ABZ sulphone] in the breast milk lactating women after one single oral dose of ABZ.

METHODS

Thirty-three lactating women (age 18–40 years) participated in the study. They received a single oral 400-mg dose of ABZ. Five milk samples were taken at 0, 6, 12, 24 and 36 h. One serum sample was taken after 6 h. Samples were analysed using high-performance liquid chromatography and pharmacokinetic analysis was performed.

RESULTS

ABZ was detectable in milk samples 6 h after the oral dose. The mean concentration of serum ABZ was 63.7 ± 11.9 ng ml⁻¹. The pharmacokinetic parameters for ABSX were calculated as follows: 351.9 ± 32.4 ng ml⁻¹, 6.9 ± 0.5 h, 12.4 ± 2.2 h and 5190.3 ± 482.8 ng*h ml⁻¹ for C_max, T_max, t_½ and AUC_0–36, respectively. The milk-to-serum ratios (range) for ABZ and ABSX were 0.9 (0.2–6.5) and 0.6 (0.1–1.5), respectively.

CONCLUSIONS

After an oral dose of 400 mg, ABZ and ABSX attain low concentrations in breast milk that are unlikely to be considered harmful for the breastfed infant.     

Pharmacokinetics of methyprylon following a single oral dose

Single oral doses of 300 mg of methyprylon were administered to 10 healthy volunteers. Plasma concentrations of methyprylon and its dehydro metabolite were measured using a recently developed HPLC assay. Plasma concentration-time data were fitted to a two-compartment model with either first-order absorption, zero-order absorption, or two consecutive, discontinuous, first-order absorption rate constants. Based on the criteria of visual inspection, the correlation coefficient, standard deviations of the parameter estimates, and the residual sum of squares, it was concluded that the zero-order absorption model fit the data best. Mean (+/- SD) values for the half-life (9.2 +/- 2.2 h), apparent clearance, (11.91 +/- 4.42 mL/h/kg) and apparent steady-state volume of distribution, (0.97 +/- 0.33 L/kg) were found.     

Distribution of dieldrin following a single oral dose

Two groups of investigators have used the classical model for the distribution of thiopental following iv injection to predict the distribution of dieldrin following accidental ingestion. They concluded that the concentration of dieldrin in the brain is reduced first by redistribution to muscle and only later by redistribution to fat. The model as originally designed for thiopental had been evaluated by analysis of samples from persons undergoing surgery under thiopental anesthesia. Since it is not appropriate to give large doses of dieldrin to humans or to collect samples of muscle and various vital organs from them, the distribution of dieldrin was studied in rats. Dieldrin dissolved in corn oil was administered to these animals by stomach tube. The highest concentration of dieldrin in the brain was reached in 4 hr, and the concentration decreased gradually thereafter. The concentration in muscle remained essentially steady during the interval from 4 to 48 hr. There was no peak for muscle that could be interpreted as replacing a peak for brain. The concentration of dieldrin in fat was already slightly higher than that in the brain at 1 hr, very much higher at 4 hr when the concentration in the brain was maximal, and the concentration in the fat continued to increase during the first 24 hr. Either on the basis of concentration or on the basis of the total amount in each organ, no reason was found to assign any special importance to muscle as a sink into which dieldrin is redistributed from the brain. The fat appears to be far more important in this regard. The results indicate the danger of applying a mathematical model to a new situation without checking the results experimentally.     

The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment

Summary Flutamide is a nonsteroidal antiandrogen used in the treatment of prostatic carcinoma. We have investigated the disposition of flutamide and its two major metabolites in ten urological in-patients without significant liver or renal disease.After oral administration flutamide is absorbed from the gastrointestinal tract with a t_max of about 2 h.Flutamide undergoes extensive first-pass metabolism, and its major metabolites are 2-hydroxyflutamide and the hydrolysis product 3-trifluoromethyl-4-nitroaniline.After the oral administration of a single dose of 250 mg or 500 mg maximum flutamide plasma concentrations of 0.02 and 0.1 µg·ml^–1 respectively were observed. Maximum plasma concentrations of 2-hydroxylfutamide for the same flutamide doses were 1.3 and 2.4 µg·ml^–1 (mean ofn=2 orn=3).Steady-state concentrations of the biologically active metabolite 2-hydroxyflutamide (0.94±0.23 µg·ml^–1, mean±SD,n=5) were found at 2–4 days after the administration of 250 mg every 8 h.The area under the plasma concentration time curve for 2-hydroxyflutamide averaged 11.4 (10.6 and 12.1) and 24.3 (21.5–29.4,n=3) µg·ml^–1·h for 250 mg and 500 mg flutamide orally.2-Hydroxyflutamide and 3-trifluoromethyl-4-nitroaniline were eliminated monoexponentially with half-times of 4.3–21.9 and 4.3–17.2 h (n=5) respectively.     

大鼠一次性灌服酸枣仁汤剂提取物后芒果苷的药代动力学研究

沈阳药科大学 药学院, 辽宁 沈阳 110016     

Metabolism of thymoxamine: identification of metabolites in rat

Thymoxamine hydrochloride administered by mouth to rats at 25 or 100 mg kg-1 was excreted in the urine as the deacetyl and N-demethyl-deacetyl metabolites. These were completely sulpho- and glucuronoconjugated at 25 mg kg-1 but only partially so at the higher dose. Thymoxamine deacetylation in vitro is catalysed by plasma and hepatic cytosol esterases and the deacetyl metabolite undergoes N-demethylation catalysed by the cytochrome P 450 hepatic microsome mixed function monooxygenase system. Because of the rapidity of the deacetylation it is concluded that thymoxamine is a prodrug leading in vivo to the active deacetyl thymoxamine.     

Metabolism of thymoxamine: identification of metabolites in rat

Thymoxamine hydrochloride administered by mouth to rats at 25 or 100 mg kg^?1 was excreted in the urine as the deacetyl and N-demethyl-deacetyl metabolites. These were completely sulpho- and glucuronoconjugated at 25 mg kg^?1 but only partially so at the higher dose. Thymoxamine deacetylation in vitro is catalysed by plasma and hepatic cytosol esterases and the deacetyl metabolite undergoes N-demethylation catalysed by the cytochrome P 450 hepatic microsome mixed function monooxygenase system. Because of the rapidity of the deacetylation it is concluded that thymoxamine is a prodrug leading in vivo to the active deacetyl thymoxamine.     

Plasma levels after a single oral dose of proscillaridin

Summary Plasma levels of proscillaridin, measured by a modified⁸⁶Rb-erythrocyte method, have been studied in 6 healthy volunteers who received single oral doses of 2.5 mg. There were two maxima in the plasma curve, one after 0.5 h (median level 410 pg/ml) and another after 10 h (median value 390 pg/ml); and, a distinct minimum at 3 h (median value 98 pg/ml). After 24 h the median plasma concentration was 305 pg/ml, and after 48 h it was 115 pg/ml.     

Pharmacokinetics of dipipanone after a single oral dose.

A single oral dose of Diconal (dipipanone HCl 10 mg, cyclizine HCl 30 mg) was given to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-1, the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h.     

Clinical pharmacokinetics after a single oral dose of oxilofrine

In a combined pharmacokinetic and clinical trial the correlation was investigated between plasma levels of oxilofrine and the haemodynamic effects on eight healthy volunteers after an oral dose of 120 mg oxilofrine. Plasma levels of free oxilofrine were measured by capillary gas chromatography mass fragmentography. Cardiovascular as well as echocardiographic parameters (left ventrical extent and velocity of fractional shortening) have been measured. The results pharmacokinetically showed a marked enterohepatic reabsorption profile with a second oxilofrine plasma peak occurring in between the second and third hours. The heart rate and mean arterial blood pressure remained unchanged. The total peripheral resistance was deceased on average. Systolic blood pressure increased by a maximum of 13.8%, the diastolic decreased by 8.8%. Increasing of the extent of left ventrical fractional shortening by 20.9% and the velocity by 29.5% indicated a positive inotropic effect, which was long lasting and not accompanied by chronotropic effects. There is a direct positive correlation between oxilofrine plasma levels and the extent of fractional shortening of left ventrical diameter (r = 0.981).     

单剂量口服盐酸曲马多在维吾尔族和汉族健康受试者体内的药代动力学研究

目的:研究盐酸曲马多在中国维吾尔族和汉族健康受试者体内的药动学。方法:选择维吾尔族和汉族健康志愿者各10名(5男5女),每名口服盐酸曲马多100mg后,用高效液相色谱荧光检测法测定受试者血浆中盐酸曲马多的血药浓度,研究其药代动力学过程,用DasVer2.0药动学软件进行数据处理。结果:汉族、维吾尔族两个民族口服盐酸曲马多后药时曲线均符合一室开放模型。主要药代动力学参数分别为:t1/(26.2±1.0)和(7.1±1.9)h,tma(x2.4±0.7)和(2.6±0.6)h,Cma(x401.4±78)和(350.6±46)μg·L-1,AUC0-3(64297.1±1261.8)和(4111.6±1336.0)μg·h·L-1,AUC0-∞(4456.1±1318.5)和(4368.5±1603.5)μg·h·L-1。结论:服用盐酸曲马多后,汉族、维吾尔族健康受试者的Cmax,AUC0-t,AUC0-∞个体间差异较大,同一民族受试者单剂量口服盐酸曲马多后的药动学参数无明显差异(P>0.05),男女受试者单剂量口服盐酸曲马多后的药动学参数在统计学上有显著性差异(P<0.05)。     

Metipranolol and propranolol: No CNS effects of a single oral dose

Effects of single oral doses of the -blocking drugs propranolol (40 mg) and metipranolol (Disorat, Boehringer, Mannheim, FRG, 5 and 20 mg), in comparison with placebo, on mental performance and psychophysiological measures were investigated in a double-blind crossover study comprising 12 healthy volunteers. Effects were evaluated using a battery of highly reliable and sensitive computerized indices of mental performance and a comprehensive range of psychophysiological measures. Propranolol and metipranolol had no effects on mental performance, in contrast to findings in a previous study for bunitrolol (Stresson, Boehringer, Ingelheim, FRG). There were marked effects on some autonomic functions; dose-dependent for heart rate and heart rate response, and dose-independent for blood pressure and finger tremor. In the previous study bunitrolol had no effect on tremor and blood pressure and a less marked effect on heart rate. The lack of psychotropic effects for metipranolol and propranolol as compared to bunitrolol cannot be predicted from pharmacokinetic properties or peripheral effects of the three drugs, arguing for the need for systematic screening using psychometric and psychophysiological methods of current and new -blocking drugs. A comparison between the effect of propranolol given in a single oral dose and findings in a previous study with repeated administration suggested that the differences in effect profile between acute and chronic administration of the drug are small.