甲氟哌酸对茶碱在家兔体内药物动力学的影响

目的：在家兔体内观察甲氟哌酸对茶碱的药物动力学的影响。方法：动物分为２组，第１组静注茶碱１２ｍｇ·ｋｇ－１，第２组静注茶碱１２ｍｇ·ｋｇ－１和甲氟哌酸２０ｍｇ·ｋｇ－１，用高效液相法测定茶碱的血药浓度，计算机拟合房室模型并计算药物动力学参数。结果：茶碱的药时曲线符合二室模型，合用甲氟哌酸后，茶碱的药时曲线消除相血药浓度显著高于单用茶碱；茶碱的消除半衰期Ｔ１／２β和曲线下面积ＡＵＣ明显增大；机体清除率ＣＬ明显降低，两组之间有显著性或非常显著性差异。结论：甲氟哌酸能延缓茶碱在兔体内的清除，提示合并用药时应对茶碱进行临床给药监测。     

Down-regulation of the hepatic cytochrome P450 by an acute inflammatory reaction: implication of mediators in human and animal serum and in the liver

1. Infection and inflammation trigger a cascade of mediators that eventually will down-regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute inflammatory reaction (AIR) induced by the s.c. injection of turpentine (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection.
2. Hepatocytes from control (H_CONT) rabbits and rabbits with an AIR (H_INFLA) were isolated and cultured. Compared with H_CONT in H_INFLA the production of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H_INFLA with serum of rabbits with an AIR (RS_INFLA) for 4 h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS_INFLA obtained 6, 12 and 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h.
3. The efficacy (E_max) of RS_INFLA to inhibit the formation of theophylline metabolites differed, i.e. 1,3DMU>1MU>3MX, and the potency of serum mediators (IC₅₀) was similar for 3MX and 1MU, but lower for 1,3DMU.
4. Incubation of serum of human volunteers (HS_INFLA) with a viral infection with H_CONT or H_INFLA reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS_INFLA depressed 1,3DMU more efficiently than 3MX and 1MU. HS_INFLA reduced 3MX with greater efficacy than did RS_INFLA. Potency was very variable but not different from rabbits.
5. It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS_INFLA or RS_INFLA is closely associated with the increase in lipid peroxidation (r²= 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 down-regulation.

     

Comparative pharmacokinetics of propranolol and atenolol in primary hyperlipidemia

The study was aimed to examine the effects of different types of hyperlipidemia on the pharmacokinetics of lipophilic propranolol and hydrophilic atenolol. Thirty subjects were divided into four study groups: normolipemics, hypercholesterolemics, hypertriglyceridemics, and patients with mixed form of hyperlipidemia. The drugs were administered orally at a single dose of 80 mg for propranolol and 100 mg for atenolol, using a cross-over study design. Pharmacokinetic parameters of the drugs were calculated using a noncompartmental open model. The results of the present study demonstrated a possible influence of dyslipidemia on pharmacokinetics of both the lipophilic and hydrophilic drugs. As for the lipophilic drug propranolol, a significant decrease in elimination rate constant was found (from 0.24 +/- 0.08 h(-1) to 0.16 +/- 0.04 h(-1), p < 0.03) in comparison to normolipemic subjects. In the case of the hydrophilic atenolol, the most marked alterations were also seen in subjects with mixed form of hyperlipidemia, especially significantly lower values of area under the concentration-time curve (8950.8 +/- 2060.5 ng/ml x h and 6715.4 +/- 1813.8 ng/ml x h, p < 0.05) as well as higher elimination rate constant (0.08 +/- 0.03 h(-1) and 0.13 +/- 0.05 h(-1), p < 0.05) in comparison with the controls, respectively. Total body clearance per kg of body weight of propranolol as well as atenolol was not influenced by dyslipidemias. The results of the study indicate that lipid metabolism disturbances might to some extent influence the pharmacokinetics of propranolol and atenolol, with the most significant alterations seen in the patients with mixed form of hyperlipidemia.     

Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease

Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.) dose of theophylline, both in patients with idiopathic Parkinson's disease (PD). Methods: Pharmacokinetic parameters (AUC and C_max) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in 12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at doses of up to 300 mg b.i.d. The parameters AUC, C_max and t_max for ropinirole were compared before, during and after oral theophylline co-treatment. Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and without ropinirole: 68.6 μg · h⁻¹ · ml⁻¹ and 70.0 μ· h⁻¹ · ml⁻¹, respectively; mean C_max with and without ropinirole: 11.07 μ g · ml⁻¹ and 11.83 μg · ml⁻¹, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h⁻¹ · ml⁻¹ and 22.09 ng · h⁻¹ · ml⁻¹, respectively; mean C_max for ropinirole with and without theophylline: 5.65 ng · ml⁻¹ and 5.54 ng · ml⁻¹, respectively; median t_max for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively). Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses. Received: 10 August 1998 / Accepted in revised form: 27 January 1999     

Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers

Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier t_max and a higher C_max and AUC were observed in the subjects who received piperine and propranolol. It produced a higher C_max, longer elimination half-life and a higher AUC with theophylline.In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.     

Pharmacokinetic study of theophylline in dogs after intravenous administration with and without ethylenediamine

Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.     

Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone

Objectives:

To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP).

Materials and Methods:

The disposition of DHP following oral (36, 72, 100 and 150 mg/kg) and intravenous (1, 5 and 10 mg/kg) administration and its dose-response relationship were carried out in Sprague–Dawley rats. DHP and its metabolite 5-pregnene-3β-ol-16, 17-epoxy-20-one (M1) were analyzed by a validated LC-MS/MS method in plasma after intravenous and oral administration. Dose escalation lipid lowering activities were carried out by triton-induced hyperlipidemic model.

Results:

Oral administration resulted in higher amount of M1 formation as compared to intravenous administration. Dose escalation intravenous administration (1, 5 and 10 mg/kg) resulted in nonlinear increase in AUC of DHP. This was due to saturation of metabolism. On the contrary, systemic AUC and C_max after oral administration show non-linear pharmacokinetics where saturated systemic DHP and M1 pharmacokinetics was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg.

Conclusion:

DHP exhibits route and dose-dependent pharmacokinetics. Pharmacokinetic and lipid lowering activity by oral route indicate saturation of oral absorption at higher doses. The study contributes to the understanding of the plasma disposition pharmacokinetics of DHP and its metabolite in rats by oral and intravenous route of administration.KEY WORDS: Dose-escalation pharmacokinetics, lipid-lowering activity, 80/574     

间硝苯地平在兔体内的药物动力学

目的：研究间硝苯地平剂量效应的药代动力学。方法：兔被随机分成３组,分别静脉注射高、中、低（０５,１,２ｍｇ／ｋｇ）３种剂量的间硝苯地平,用ＨＰＬＣ法测定血浆药物浓度。结果：间硝苯地平的血药浓度和时间数据经拟合均符合二室模型,主要药动学参数如下（以剂量１ｍｇ／ｋｇ为例）：Ｖｄ＝０３７Ｌ／ｋｇ,Ｔα／２＝６４ｍｉｎ,Ｔβ／２＝８４１ｍｉｎ,ＡＵＣ＝９４１ｍｇ·ｍｉｎ／Ｌ,ＣＬ＝０６５Ｌ／（ｋｇ·ｈ）。各剂量组间的ＣＬ,Ｔβ／２经方差分析无显著差异,用单位体重的曲线下面积对剂量进行线性回归存在显著正相关。结论：间硝苯地平分布广,消除也迅速;在剂量０５～２ｍｇ／ｋｇ范围内消除动力学呈非剂量依赖性关系。     

Model-based analysis of thromboxane B2 and prostaglandin E2 as biomarkers in the safety evaluation of naproxen

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C_max and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B₂ and prostaglandin E₂ were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB₂ and PGE₂ was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies.     

Studies on the pharmacokinetics and pharmacodynamics of propranolol in hyperlipidemia.

The lipophilic beta-adrenoreceptor antagonist propranolol has been studied to define its pharmacokinetic and pharmacodynamic characteristics in hyperlipidemic patients. A total of 48 subjects were allocated to four study groups: (1) healthy volunteers, (2) hypercholesterolemic patients, (3) hypertriglyceridemic subjects, and (4) patients with a mixed form of hyperlipidemia. Propranolol was given orally as a single dose of 80 mg. Heart rate was measured during 12 hours. At each point, the concentrations of propranolol were estimated. Moreover, heart rate and arterial systolic blood pressure were examined at rest and after a submaximal exercise test 3 hours after administration of propranolol (i.e., at the peak of propranolol concentration in the blood serum). A significant increase in the area under the serum concentration-time curve (AUC) by 39% and a reduction of the volume of distribution and total body clearance by 48% and 46%, respectively, without a significant change in the half-life time, were observed in patients with hypertriglyceridemia in comparison with the control group. The acceleration of exercise heart rate and the elevation of systolic blood pressure were comparable in all groups in the study, whereas blood serum concentrations of propranolol in patients with hypertriglyceridemia (group 3) and the mixed form of hyperlipidemia (group 4) were markedly altered from those observed in normolipemic subjects. No relationship between the concentration of propranolol and the heart rate in the group with hypertriglyceridemia was seen. In the light of this study, the authors suggest that lipid metabolism disturbances do not affect the pharmacodynamics of propranolol.     

七叶皂苷对洛伐他汀在高脂血症大鼠模型体内药代动力学的影响

目的在高脂血症大鼠模型中研究七叶皂苷对洛伐他汀药代动力学的影响。方法采用高脂饲料喂饲大鼠,构建高脂血症大鼠模型,通过血清生化分析确定造模成功。选择12只造模成功的大鼠,随机分成2组,即单独给药组和联合给药组,每组6只大鼠。单独给药组和联合给药组大鼠分别经尾静脉注射给予0.9%生理盐水和注射用七叶皂苷钠(0.5 mg/kg,qd),连续14 d。第14天,给药后,两组大鼠灌胃给予洛伐他汀(20 mg/kg,0.5%CMC-Na溶液),并于洛伐他汀给药前和给药后不同时间点采集血样,采用HPLC-MS/MS方法测定洛伐他汀及其活性代谢物洛伐他汀酸的血药浓度,计算药动学参数。结果长期给予七叶皂苷钠导致洛伐他汀酸的血浆暴露水平显著升高,Cmax、AUC0-t、AUC0-∞分别是单独给药组的2.43(90%CI:1.55,3.31)、2.66(90%CI:1.67,3.66)和2.99倍(90%CI:1.44,4.55),两组比较差异有统计学意义(P<0.05)。与单独给药组相比,联合给药组洛伐他汀的血浆暴露也略有增加,但两组Cmax和AUC比较差异无统计学意义(P>0.05)。结论七叶皂苷可抑制高脂血症模型大鼠的洛伐他汀代谢,增加其体内暴露水平。     

Effects of lansoprazole on pharmacokinetics and metabolism of theophylline

The effect of the new substituted benzimidazole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated.After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t _1/2) or the mean residence time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CL_app). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t _1/2 and about 10% in the MRT of theophylline, although neither AUC nor CL_app showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU.The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.     

An evaluation of the dose-dependent inhibition of CYP1A2 by rofecoxib using theophylline as a CYP1A2 probe

This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.     

The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

The response of cyclosporine A (CyA) blood concentrations following changes in lipoprotein levels have been inconsistent. Some studies show increases in concentrations, whereas others have shown decreases. The intent of this study was to examine the effect of two rat models of increased lipoprotein on the pharmacokinetics of CyA. One was a simulated high fat content meal, in which 1% cholesterol in peanut oil was administered. The other was the poloxamer 407-induced model of hyperlipidemia. Rats in these two groups were compared to a group fasted overnight before the study. In rats given a simulated high fat meal, at most time points the mean blood and plasma concentrations were lower, though not significantly, compared to fasted animals. Oral lipid led to no significant changes in the measured pharmacokinetic parameters of blood or plasma area under the concentration vs time curve (AUC), clearance (CL), volume of distribution (Vd) or plasma unbound fraction. In the poloxamer 407-treated hyperlipidemic rats there were significant reductions in plasma unbound fraction plasma, Vd and terminal half-life, but not AUC or CL, compared to normolipidemic rats. In contrast, the CL, Vd and t1/2 in the oral lipid-fed rats were all significantly higher than the poloxamer 407 treated animals. Oral absolute bioavailability of CyA was unchanged by oral lipid. In humans and rats the pharmacokinetics of CyA in the face of increased lipoprotein levels do not correspond well to what is typically seen for other drugs that are known to bind to lipoproteins.     

Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline

AIM: To study the potential pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline at steady state. METHODS: Theophylline 200 mg extended-release formulation was administered twice daily on days 1-11 to 30 healthy, non-smoking males. On days 5-11, 15 subjects received concomitant lansoprazole 30 mg once daily (o.d.) and 15 subjects received concomitant pantoprazole 40 mg o.d. RESULTS: No significant changes in the steady-state theophylline maximum plasma concentration (Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin), area under the plasma concentration-time curve over the 12-h dosing interval (AUC0-12), or apparent total oral clearance (CL/F) were observed within the two treatment groups when theophylline was administered alone or in combination with lansoprazole or pantoprazole. In addition, no significant differences in the changes of steady-state theophylline pharmacokinetics from day 4 to day 11 were noted between the two treatment groups. Treatment with theophylline in combination with either lansoprazole or pantoprazole was well tolerated. All adverse events were transient and rated mild to moderate in severity. CONCLUSION: Co-administration of either lansoprazole or pantoprazole in healthy subjects does not significantly affect the steady-state pharmacokinetics of theophylline at the therapeutic doses tested.     

Depression of theophylline metabolism and elimination by troleandomycin and erythromycin

Clinical observations have suggested that elevated levels of theophylline may occur during the use of macrolide antibiotics. In the present study, the plasma clearance of theophylline was studied in rabbits treated with troleandomycin or erythromycin (400 mg · kg^?1 · day^?1) over a 10-day period. The elimination of theophylline was impaired significantly after 10 days of antibiotic treatment. No change in theophylline elimination occurred when the antibiotics were given for shorter periods of time. Protein, cytochrome P-450 and cytochrome b₅ levels, and aminopyrine N-demethylase and benzo[α]pyrene hydroxylase activities were unchanged in hepatic microsomes prepared from rabbits treated with antibiotics for 10 days. Pretreatment of rabbits for 10 days with troleandomycin completely abolished production of 1-methyluric acid from theophylline in isolated hepatic microsomes, but production of 1,3-dimethyluric acid was unaffected. Troleandomycin, when added in vitro to microsomes, had no direct effect on theophylline metabolism. It is concluded that long-term treatment with troleandomycin selectively blocks or destroys one pathway of theophylline metabolism. This mechanism may explain the clinically observed interaction between theophylline and the macrolide antibiotics.     

茶多酚对家兔血脂的影响

目的观察茶多酚在高脂血症形成过程中对家兔血脂的影响。方法24只家兔随机分为正常组、高脂对照组、0.2%茶多酚组和0.4%的茶多酚组。除正常组外,各组家兔均喂饲高脂饲料。0.2%茶多酚组和0.4%的茶多酚组在给予家兔高脂饲料的同时,分别在饮水中添加0.2%、0.4%的茶多酚,连续喂养12周;分别于实验前、6周末和12周末心脏穿刺取血测定家兔血清甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)水平。结果茶多酚组家兔血清TG、TC、LDL明显低于高脂对照组,HDL则高于高脂对照组(P<0.05)。结论茶多酚具有一定的调节血脂代谢的作用。     

Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life (t_1/2) in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67±4.85%) decreased about four-folds, but in DMNA (73.00±9.85%) similar result, was observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.     

An interspecies extrapolation of the pharmacokinetics of telavancin, a rapidly bactericidal, concentration-dependent antibiotic

Telavancin is an intravenous lipoglycopeptide antibiotic active against many Gram-positive pathogens via inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function. Non-compartmental pharmacokinetic parameters of telavancin (clearance [Cl], steady-state volume of distribution [Vss], area under the concentration curve [AUC], and elimination half-life [t(1/2)]) were determined for five preclinical species (mice, rats, rabbits, dogs, and monkeys). Interspecies scaling was applied to predict the corresponding parameters in humans and compare retrospectively with observed values. Plasma concentrations of single doses of telavancin declined monoexponentially in all species with half-lives between 1.2 and 2.4?h. The pharmacokinetics of telavancin was demonstrated to be dose-proportional in rabbits and gender-independent in monkeys. Application of the simple allometric equation (Y?=?aW(b)) resulted in a good correlation between predicted and observed values of Vss in humans. Application of a modified allometric equation that includes brain weight (Cl?×?BW?=?aW(b)) resulted in a good correlation between predicted and observed values of Cl, AUC, and t(1/2) in humans. These data suggest that interspecies scaling may be useful to predict pharmacokinetic parameters of telavancin in humans.     

罗红霉素对兔体内稳态时氨茶碱药代动力学的影响

目的　观察 6只新西兰白兔灌服罗红霉素前后对氨茶碱稳态血药浓度及药代动力学的影响。方法　实验分二期 :Ⅰ期为d 1～ 4单独灌服氨茶碱至稳态 ;Ⅱ期为d 5～ 10合用罗红霉素与氨茶碱 ,血药浓度采用HPLC法测定。结果　各期测得氨茶碱药代动力学参数 ,与Ⅰ期比较 ,Ⅱ期的AUC、CL/Fs、Ka、Ke、T1/ 2 (ka) 、Tmax差异有显著性 (P <0 0 5 ,P <0 0 1) ,而Cmax、V/Fc、T1/ 2 (ke) 在两期间差异均无显著性(P >0 0 5 )。结论　长期合用罗红霉素和氨茶碱 ,罗红霉素能延缓氨茶碱在兔体内稳态时的吸收和消除 ,提示合并用药时应对氨茶碱进行临床给药监测。