Pharmacokinetics and tissue disposition of danofloxacin in sheep

The plasma pharmacokinetics of danofloxacin administered at 1.25 mg kg⁻¹ body weight by the intravenous and intramuscular routes were determined in sheep. Tissue distribution was also determined following administration by the intramuscular route at 1.25 mg kg⁻¹ body weight. Danofloxacin had a large volume of distribution at steady state (V_ss) of 2.76±0.16 h (mean±S.E.M.) L kg⁻¹, an elimination half-life (t_1/2β) of 3.35±0.23 h, and a body clearance (C1) of 0.63±0.04 L kg⁻¹ h⁻¹. Following intramuscular administration it achieved a maximum concentration (C_max) of 0.32±0.02 μg mL⁻¹ at 1.23±0.34 h (t_max) and had a mean residence time (MRT) of 5.45±0.19 h. Danofloxacin had an absolute bioavailability (F) of 95.71±4.41% and a mean absorption time (MAT) of 0.81±0.20 h following intramuscular administration. Mean plasma concentrations of >0.06 μg mL⁻¹ were maintained for more than 8 h following intravenous and intramuscular administration. Following intramuscular administration highest concentrations were measured in plasma (0.43±0.04 μg mL⁻¹), lung (1.51±0.18 μg g⁻¹), and interdigital skin (0.64±0.18 μg g⁻¹) at 1 h, duodenal contents (0.81±0.40 μg mL⁻¹), lymph nodes (4.61±0.35 μg g⁻¹), and brain (0.06±0.00 μg mL⁻¹) at 2 h, jejunal (10.50±4.31 μg mL⁻¹) and ileal (5.25±1.67 μg mL⁻¹) contents at 4 h, and colonic contents (8.94±0.65 μg mL⁻¹) at 8 h. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics of intravenous and epidural ropivacaine in the rhesus monkey

Ropivacaine is a new long-acting amide local anesthetic which is possibly less cardiotoxic than bupivacaine. The absorption and disposition of ropivacaine were characterized in six rhesus monkeys in an open two-way crossover study following intravenous and epidural administration. For these studies, animals were anesthetized for placement of intravenous and intraarterial catheters. For the epidural studies, a PE-10 catheter was also inserted 3 cm into the lumbar epidural space. After recovery from anesthesia, animals received ropivacaine 1 mg kg^?1 intravenously over 1 min or 10 mg of ropivacaine epidurally (two 1 ml doses of 0.5, 5 min apart), and arterial blood samples were obtained over 5 h. Serum ropivacaine concentrations were determined by gas chromatography with NP detection. Concentration—time data following i.v. and epidural administration were fitted simultaneously. Initial parameter estimates were obtained by analyzing each route separately. Input rates and their corresponding extent of absorption were estimated using deconvolution. Mean (±SD) disposition parameters included: V_ss = 1.11±0.198 1kg^?1; CL = 0.711 ± 0.158 1 h^?1 kg^?1; t_1/2,z = 2.07 ± 0.438 h. Mean (± SD) absorption parameters included: F₁ = 0.506 ± 0.221; t = 0.060 ± 0.078 h; F₂ = 0.444 ± 0.182; t = 6.45 ± 11.09h. Ropivacaine's biphasic absorption and bioavailability are similar to those of other amide local anesthetics. The biphasic absorption may be related to partitioning into fat or regional changes in blood flow induced by the drug.     

Repeated dose pharmacokinetics of pancopride in human volunteers

The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL^?1. The maximum plasma concentration (mean ± SD) after the first dose was 92.5 ± 41.5 ng mL^?1 and t_max was 1.7 ± 0.9 h. The elimination half-life (t_1/2) was 14.3 ± 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 ± 396 ng h mL^?1. The maximum plasma concentration (mean ± SD) at steady state (day 5) was 101.8 ± 36.9 ng mL^?1 and t_max was 2.2 ± 1.2 h. The elimination half-life (t_1/2) was 16.3 ± 2.7 h and the minimum plasma concentration (C) was 16.6 ± 6.9 ng mL^?1. The area under the concentration-time curve during the dosing interval (AUC) was 995 ± 389 ng h mL^?1. The average plasma concentration at steady state (C) was 43.3 ± 16.1 ng mL^?1 and the experimental accumulation ratio (R_AUC) was 1.34 ± 0.19, whereas the mean theoretical value (R) was 1.40 ± 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration. The safety parameters showed no clinically relevant alterations.     

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M₁) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M₁ was administered as a single 5 mg kg⁻¹ dose intravenously (iv) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M₁ and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M₂). The t_1/2 and AUC of M₁ and M₂ were 2.1±0.5 and 3.0±1.1 h, and 1300±200 and 240±37 ng h mL⁻¹, respectively. The Cl and Cl_r of M₁ were 60±10 and 0.81±0.63 mL min⁻¹ kg⁻¹, respectively. M₁ significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p <0.05), but had no significant effect on the heart rate (p >0.05). The E_max and EC₅₀ as estimated by the inhibitory sigmoidal E_max model were 20±18% 620±310 ng mL⁻¹, respectively for SBP; 20±8.3% and 420±160 ng mL⁻¹ for DBP. © 1998 John Wiley & Sons, Ltd.     

Time course of cyclosporine and its metabolites in blood,liver and spleen of naive lewis rats: Comparison with preliminary data obtained in transplanted animals

The time course of intravenously administered cyclosporine (1mg kg^?1) and its metabolites AM1, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration versus time data for all three tissues were qualitatively similar, following a biexponential model C = Ae + Be with maximum cylosporine concentrations reached at 1h. Whole-blood cyclosporine clearance, terminal half-life, mean residence time, steady state volume of distribution, and hepatic extraction ratio (calculated from blood data) were similar to previously reported results. Cyclosporine in the liver showed the largest area under the concentration—time curve, mean residence time, and disposition and terminal half-lives. Spleen cyclosporine mean residence time and terminal half-life were not significantly different from blood parameters. Metabolites AM1, AM9, and AM1c showed almost parallel time courses in all three tissues. The hydroxylated derivative AM9 was the major metabolite found in all tissues, with twofold greater levels in the liver compared to the blood and the spleen. Slightly less AM1 was found in the liver relative to blood and spleen, where it was present in equal amounts. AM1c levels in the liver were not different from those in the spleen and were greater than observed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AM1, and AM9 post-transplant showed twofold to fourfold decreases from day 3 (samples taken 4h post-CyA-dose) to day 7 (samples taken 24h post-CyA-dose) and concentrations were not significantly different from similarly sampled naive controls. More importantly, the metabolite/CyA ratios did not vary significantly between liver and blood in the two groups. For naive rats, and liver transplanted animals not undergoing rejection, changes in blood cyclosporine levels seem to predict variations in tissue concentrations.     

Disposition and bioavailability of the β1-adrenoceptor antagonist talinolol in man

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective β₁-adrenoceptor antagonist talinolol (Cordanum®—Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (C_max) of 631 ± 95 ng mL^?1 (mean ± SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC_0-∞) was 1433 ± 153 ng h mL^?1. The following parameters were estimated: terminal elimination half life (t_1/2), 10.6 ± 3.3 h; mean residence time, 11.6 ± 3.1 h; volume of distribution, 3.3 ± 0.5 L kg^?1; and total body clearance, 4.9 ± 0.6 mL min^?1 kg^?1. Within 36 h 52.8 ± 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 ± 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a C_max of 168 ± 67 ng mL^?1 was reached after 3.2 ± 0.8h. The AUC_0-∞ was 1321 ± 382 ng h mL^?1. The t_1/2 was 11.9 ± 2.4 h. 28.1 ± 6.8% of the dose or 55.0 ± 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 ± 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 ± 15% (95% confidence interval, 36–69%). Talinolol does not undergo a relevant first-pass metabolism, and its reduced bioavailability results from incomplete absorption. Talinolol disposition is not found to be altered in poor metabolizers of debrisoquine type.     

Influence of concentration-dependent protein binding on serum concentrations and urinary excretion of disopyramide and its metabolite following oral administration

Concentrations of disopyramide (D) and mono-N-dealkyldisopyramide (MND) were measured in serum and urine following administration of 100, 150, 200, and 300 mg D to four volunteers. The free fraction of D in serum was drug concentration-dependent in all four subjects following the administration of the four doses. Areas under the free (unbound) D serum concentration-time curves (AUC) were linearly related to dose following 100–200 mg D. AUC values were 30–60 per cent higher than expected in two subjects following 300 mg D due to an apparent dose-dependent decrease in D renal tubular secretion. Renal clearance of free D averaged 10·91h^?1. The renal clearance of MND averaged 10·31h^?1. The urinary excretion of MND was proportional to disopyramide dose.     

THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for C_min (mean (SD)=47·2 (25·8) against 39·6 (21·1) ng mL⁻¹, p=0·038), AUC_0–24 (2008 (814) against 1754 (714) ng h mL⁻¹, p=0·024), and AUC_0–48 (2662 (1244) against 2395 (238) ng h mL⁻¹, p=0·034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.     

Wastewater toxicity assessment using the electrophysiological response of a charophyte Nitellopsis obtusa

A biotesting method for the assessment of acute sublethal toxicity to charophyte cells of Nitellopsis obtusa was developed and applied for the study of Vilnius and Visaginas wastewaters (WW). This computer-assisted testing procedure was based on the recording of the electrophysiological response of up to 16 single algal cells simultaneously. Membrane parameters of living cells were measured according to the K⁺-anaesthesia method modified for multichannel recording with extracellular electrodes. Concentration-dependent monotonical decrease of cell resting potential, induced by toxic WW action, was used to determine an effective concentration (EC) values. A multistep time-saving procedure, when the cell group was exposed to subsequent treatment with increasing WW concentrations (30 min per treatment), proved to be adequate for biotesting. The ECs obtained by this procedure were in good agreement with those obtained alternatively by undertaking one-step testing (i.e., 60 min exposure per concentration per cell group). The relative sensitivity of the cellular electrophysiological response, as a toxicity end point, was confirmed by comparing it with lethal concentration (LC) responses in 96- and 192-h exposure tests conducted on the same N. obtusa cells. For Vilnius WW samples taken on different dates, the EC ranged from 27 to 46% WW and corresponded to 96-h LC of 28–50% WW. In contrast, Visaginas WWs sampled before and after chlorination showed no toxic effect either at the membrane or whole cell level. © by John Wiley & Sons, Inc.     

Pharmacokinetics of the antiarrhythmic agent tiracizine: Steady state kinetics in comparison with single-dose kinetics

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, C_max,ss = 391.8 ng mL^?1 against C_max,sd = 132.8 ng mL^?1; M2, C_max,ss = 143.2 ng mL^?1 against C_max,sd = 25.8 ng mL^?1). However, significant increases of AUC (AUCτ = 261.9 ng h mL^?1 against AUC_0–∞,sd = 182.9 ng h mL^?1), C_max (C_max,ss = 75.9 ng mL^?1 against C_max,sd = 56.9 ng mL^?1) and t_1/2β (t_1/2β,ss = 4.0 h against t_1/2β,sd = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the t_max of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.     

PHARMACOKINETIC–PHARMACODYNAMIC MODELLING FOR CAPTOPRIL IN HEALTHY ANAESTHETIZED PIGLETS

The use of the angiotensin converting enzyme inhibitor, captopril, specially in children, has been empirical. This is because the relationship between the pharmacokinetics and pharmacodynamics of captopril has not been clearly defined. It is not usually feasible to obtain the serial kinetic–dynamic data necessary to study this relationship in infants. The piglet was therefore investigated as an animal model in which to study the relationship between the kinetics and dynamics of captopril. The standard pharmacokinetic parameters for captopril in healthy anaesthetized piglets were found to be within the range reported for humans. Cl_TB was estimated to be 1·42±0·33 L h⁻¹ kg⁻¹; t_1/2 was 0·44±0·08 h; V_dss was calculated to be 0·64±0·13 L kg⁻¹; t_1/2 and AUC_0–∞ was estimated to be 145±27 ng h mL⁻¹. The observed haemodynamic response was qualitatively similar to that in humans. Aortic pressure was reduced by 42±18%; heart rate was reduced by 21±11%. A parametric pharmacokinetic (two-compartment)–pharmacodynamic (linear) model has been established to describe plasma captopril concentration and aortic pressure relationship. Based on the observed results, the piglet was considered to be a viable model for our purpose.     

Comparison of HT29-18-C1 and Caco-2 Cell Lines as Models for Studying Intestinal Paracellular Drug Absorption

Purpose. To compare the permeability characteristics of HT29-18-C₁ colonic epithelial cell line with Caco-2, an established model of intestinal drug transport. Methods. Cell lines were grown as epithelial monolayers. Permeability was measured over a range of transepithelial electrical resistance (R_t) using a group of drug compounds. Results. HT29-18-C₁ develop R_t slowly when grown in culture, allowing permeability to be measured over a wide range (80–600 ·cm²). In contrast, Caco-2 monolayers rapidly develop R_t of 300 ·cm² and require Ca²⁺-chelation to generate R_t equivalent to human intestine (60–120 ·cm²). Permeability of atenolol, ranitidine, cimetidine, hydrochlorothiazide and mannitol across HT29-18-C₁ decreased 4–5 fold as R_t developed from 100–300 ·cm² indicating they permeate via the paracellular route. In contrast, ondansetron showed no difference in permeability with changing R_t consistent with transcellular permeation. Permeability profiles across low R_t HT29-18C₁ and pulse EGTA-treated Caco-2 monolayers were the same for all 5 paracellular drugs suggesting that transient Ca²⁺ removal does not alter selectivity of the tight junctions. Permeabilities of cimetidine, hydrochlorothiazide and atenolol across 100 ·cm² HT29-18-C₁ monolayers reflect more closely those reported for the human ileum in vivo than did mature Caco-2 monolayers. Conclusions. HT29-18-C₁ monolayers can be used to study drug permeability at R_t values similar to human intestine without the need for Ca²⁺ chelation. As such, they offer a useful alternative to Caco-2 for modelling intestinal drug absorption.     

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube

Aims

To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers.

Methods

In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, ${\text{AUC}}_{0 - \infty } Aims  To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. Methods  In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, , t_?, k_e, t_max) were compared statistically, and C_max, and t_max were analyzed for bioequivalence. Results  A statistically significant difference was seen in the of bromazepam, with nasogastric administration decreasing availability by about 25%: AUC_OR = 2501 ng mL⁻¹ h; AUC_NT = 1855 ng mL⁻¹ h (p < 0.05); ratio (geometric mean) = 0.74 [90% confidence interval (CI) 0.64–0.87]. However, this does not appear to be clinically relevant given the usual dosage range and the drug’s half-life (approx. 30 h). A large interindividual variability in omeprazole parameters prevented any statistical conclusion from being drawn in terms of both modes of administration despite their similar average profile: AUC_OR = 579 ng mL⁻¹ h; AUC_NT = 587 ng mL⁻¹ h (p > 0.05); ratio (geometric mean) = 1.01 (90% CI 0.64–1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUC_OR = 37 μg mL⁻¹ h; AUC_NT = 41 μg mL⁻¹ h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98–1.28). Conclusion  The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drugs.     

Serum theophylline levels after use of an anhydrous crystalline theophylline suppository

Summary The absorption of theophylline from a suppository not containing ethylenediamine was tested in 9 healthy volunteers. AUC after rectal administration of anhydrous crystalline theophylline 250 mg (AUC_rectal) was compared with the AUC after oral administration of microcrystalline theophylline 250 mg (Nuelin^®; AUC_oral) in a randomized, cross-over study. The ratio AUC_rectal/AUC_oral was 0.75 at 10 h, and the ratio AUC_rectal×_rectal/AUC_oral×_oral extrapolated to infinite time was 0.83. A mean concentration of 5.7 µg/ml was reached 3.7 h after a single rectal dose. The absorption studies were performed with suppositories stored for 15 weeks at 22 °C. No effect on the in vitro release rate of theophylline from the suppository was observed during storage at room temperature from 3 to 31 weeks after production. Since aminophylline suppositories are known to decompose upon storage, the results suggest that a formulation without ethylenediamine is preferable for the rectal administration of theophylline.     

Pharmacokinetic changes of M1, M2, M3 and M4 after intravenous administration of a new anthracycline,DA-125, to rats pretreated with phenobarbital, 3-methylcholanthrene,chloramphenicol, or SKF-525A

The pharmacokinetics of M1–M4, the metabolites of a new anthracycline antineoplastic agent, DA-125, were compared after intravenous (IV) administration of DA-125, 15 mg kg⁻¹, to rats pretreated with enzyme inducers, such as phenobarbital (PBT, n = 14) and 3-methylcholanthrene (MCT, n = 15), or enzyme inhibitors, such as SKF-525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After IV administration of DA-125, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous formation of M2 from M1. The AUC_{0–8 h} of M1 (47.1 versus 7.85 μg min mL⁻¹) and M2 (20.7 versus 44.3 μg min mL⁻¹) decreased significantly in the PBT group compared to those in the PBC group. However, the corresponding value of only M1 (74.6 versus 89.9 μg min mL⁻¹) decreased significantly in the MCT group. The above data indicate that metabolism of M1 is increased by pretreatment with both PB and 3-MC, and that of M2 with PB, but not with 3-MC. The AUC_{0–8 h} of both M1 (126 versus 78.5 μg min mL⁻¹) and M2 (69.2 versus 44.3 μg min mL⁻¹) increased significantly in the SKT group compared to the SKC group. However, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of both M1 and M2 is inhibited by pretreatment with SKF-525A, but not with CM. © 1998 John Wiley & Sons, Ltd.     

PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg⁻¹of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 μg kg⁻¹ are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg⁻¹. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min⁻¹, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg⁻¹ of IV MK-462. However, as the dose increased from 60 to 90 μg kg⁻¹, the mean value of the apparent CL decreased from 1376 to 807 mL min⁻¹. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg⁻¹ of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min⁻¹, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL⁻¹, 77 ng mL⁻¹, 1·6 h, and 1·8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by ≈20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C_max and apparent t_½ of MK-462.     

LC-MS测定大鼠脑脊液与血浆中西达本胺浓度及其药动学研究

目的建立快速检测SD大鼠脑脊液和血浆中西达本胺浓度的LC-MS测定方法,并应用于大鼠静脉注射西达本胺后的脑脊液和血浆中药动学研究。方法对建立的检测大鼠脑脊液和血浆中西达本胺浓度的LC-MS分析方法进行专属性、精密度、准确性、基质效应及稳定性等考察验证。♂SD大鼠12只,分为2组,每组6只,分别静脉注射给予西达本胺3,6 mg·kg^–1剂量,于给药后0.083,0.25,0.5,1,1.5,2,3 h采集脑脊液和血浆,采用LC-MS测定大鼠脑脊液和血浆中西达本胺的浓度变化,并利用DAS药动学软件拟合脑脊液和血浆中AUC、C_max、T_max、t_1/2等主要药动学参数,计算血脑屏障透过率。结果方法学研究显示,大鼠脑脊液中西达本胺线性范围为0.2～64 ng·mL^–1(r=0.999 0,定量下限为0.2 ng·mL^–1),血浆中西达本胺的线性范围为2～1 000 ng·mL^–1(r=0.999 1,定量下限为2 ng·mL^–1     

Biliary secretion of sulindac and metabolites in man

The biliary secretion of sulindac and metabolites after a single 400 mg oral dose of the drug was studied in 3 elective gallbladder surgical patients following placement of an occludable T-tube in the common bile duct. Bile and systemic plasma were sampled at frequent intervals for up to 36 h postdose. The apparent biliary clearance (V?_cl,bilc) of the prodrug sulindac is about 25 times greater than that of the pharmacologically active sulfide metabolite. The total biliary flux of drug in normal man with an uninterrupted enterohepatic cycle, calculated from V?_cl,bile and historic mean plasma drug AUC values, averages 144 and 12·2 per cent of the dose as sulindac and the sulfide metabolite, respectively. Thus, enterohepatic recycling of the drug in man is principally in the form of the prodrug which not only limits exposure of the intestine to the active moiety but also sustains systemic concentrations of active drug upon reabsorption of the prodrug.     

Effects of heavy metals on the biology of a N2-fixing cyanobacterium Anabaena doliolum

The effects of copper, nickel, and iron on survival, growth, nutrient uptake (NH, NO, and PO), carbon fixation, nitrate reductase, nitrogenase (CH₂ reduction assay), glutamine synthetase (transferase), and alkaline phophatase activities of Anabaena doliolum were studied. About 50% survival of the test alga was scored at 8.0 × 10^?3, 8.6 × 10^?3, and 0.36 mM of Cu, Ni, and Fe, respectively. However 45, 59, and 57% reductions in final yield were scored, respectively, at LD₅₀ concentrations of Cu, Ni, and Fe. On the basis of the LD₅₀ of the test metals, Ni was the most inhibitory for nutrient uptake. However, the LD₅₀ concentrations of Cu, Ni, and Fe showed different levels of inhibition for different processes. Although metal concentrations higher than LD₅₀ were found to be more inhibitory, 0.54 mM iron generated maximum inhibitory effect as compared to Cu and Ni. The present study demonstrates that the test cyanobacterium exhibits metal and dose-specific responses toward different physiological and biochemical processes.     

Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally-induced renal impairment

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg^?1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K₁₂, K₁₂, K_a and an increase in V_d and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK₁₃ and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.