Once-a-Day Oral Dosing Regimen of Cyclosporin A: Combined Therapy of Cyclosporin A Premicroemulsion Concentrates and Enteric Coated Solid-State Premicroemulsion Concentrates

Purpose. To develop once-a-day oral dosing regimen that provides the blood levels of cyclosporin A (CsA) in the therapeutic ranges over 24 hours. Methods. CsA premicroemulsion concentrates (preME) were formulated from phase diagrams. Enteric-coated solid-state premicroemulsion concentrates (sME) were prepared by coating preME with enteric-coating matrials and solidifying them. CsA was measured using high-performance liquid chromatography or radioimmunoassay. Results. PreME consisted of CsA, oil, and mixture of surfactants and a cosurfactant. PreME spontaneously formed microemulsions in aqueous medium and showed oral absorption profiles similar to Sandimmune Neoral® in dogs. Dispersion of sME in aqueous medium also formed microemulsions. Release rates of CsA from sME depended on pH and the type of enteric-coating materials and highly correlated with the extent of oral absorption. The co-administration of preME and sME (200 mg CsA) showed the maximum blood level of CsA not significantly different from that of preME (100 mg CsA) and the concentration of CsA close to the minimum therapeutic level at 24 hours. Conclusions. The combined treatment of preME and sME provided controlled oral absorption of CsA over a 24-hour period. Such once-a-day dosing regimens will lead to increased patient compliance and reduced episodes of organ rejection after transplantation.     

Tissue Distribution of [14C]Sucrose Octasulfate following Oral Administration to Rats

Purpose. Aluminum sucrose octasulfate (SOS) is used clinically to prevent ulcers. Under physiologic conditions, the sodium salt of this drug can be formed. Our objective was to determine whether sodium SOS was absorbed when administered orally. In addition to furthering our understanding of aluminum SOS, this study also aimed to clarify how other polyanionic drugs, such as heparin and low-molecular-weight heparins, are absorbed. Methods. [¹⁴C]-labeled and cold sodium SOS (60 mg/kg) were given to rats by stomach tube. Radioactivity was counted in gut tissue, gut washes, and nongut tissue (i.e., lung, liver, kidney, spleen, endothelial, and plasma samples) at 3 min, 6 min, 15 min, 30 min, 60 min, 4 h, and 24 h, and in urine and feces accumulated over 4 h and 24 h. Results. Peak radioactivity was found in the tissue and washes of the stomach, ileum, and colon at 6 min, 60 min, and 4 h, respectively, showing progression through the gut. Gut recovery accounted for 84% of the dose at 6 min but only 12% of the dose at 24 h, including counts from feces. Radioactivity was recovered from nongut tissue (averaging 8.6% of the dose) and accumulated urine (18% of the dose at 24 h). When total body distribution was considered, the recovery of radioactivity was greater for the endothelium than for plasma (peak percentage of the dose was 65% at 15 min, 20% at 3 min, 5% from 20 to 240 min for the vena cava, aortic endothelium, and plasma, respectively). Conclusions. Results indicate that sodium SOS is absorbed, agreeing with previous studies demonstrating the oral absorption of other sulfated polyanions. Endothelial concentrations must be considered when assessing the pharmacokinetics of these compounds. The measured plasma drug concentrations reflect the much greater amounts of drug residing with the endothelium.     

Passive absorption of fentanyl from the fentanyl HCl iontophoretic transdermal system

ABSTRACT

Background: The fentanyl HCl iontophoretic transdermal system (ITS) is a patient-controlled analgesic delivery system that actively administers bolus doses of fentanyl transdermally upon patient activation.

Objective: To determine the amount of fentanyl absorbed from fentanyl ITS via passive absorption over a 24.5-h period.

Methods: Serial blood samples for pharmacokinetic analyses were obtained from healthy adults who received fentanyl ITS for 24?h.

?Findings: The average absorption rate was 2.3?µg/h. An average total of 57.4?µg fentanyl was absorbed during the study. The mean maximum observed serum fentanyl concentration was 0.06?ng/mL.

Conclusions: Results indicate that the average amount of fentanyl absorbed passively or via passive delivery from fentanyl ITS is minimal. Maximum serum fentanyl concentrations fell below the range associated with analgesia and respiratory depression. The variability in fentanyl exposure was likely exaggerated by the low amounts of drug absorption resulting in overall fairly low fentanyl concentrations.     

Comparative evaluation of cyclosporine A/HPβCD-incorporated PLGA nanoparticles for development of effective ocular preparations

To improve poor water solubility of cyclosporine A (CsA), hydroxypropyl-beta-cyclodextrin (HPβCD) was incorporated into the nanoparticle formulation. Solid complexes of CsA with HPβCD in different ratios were prepared by the kneading method. CsA containing alone or in combination with HPβCD in poly-lactide-co-glycolide (P-CsA or P-CsA-HPβCD) nanoparticles were prepared by the emulsification solvent evaporation method. The mean size of CsA-loaded NPs was found to be approximately 220?nm. The solubility of CsA was significantly improved and the phase solubility diagram of CsA–HPβCD systems showed an A_L type phase. Nanoparticles showed high CsA encapsulation efficiency (88%) and production yield (89%). Release rate was increased by the presence of HPβCD and total cumulative release ranged from 75% to 96% in 24?h. In vitro cytotoxicity study assay resulted in a low toxicity for all types of nanoparticles. After 6?h incubation period, the cellular uptake was found at 33% and 32% for P–CsA and P–HPβCD–CsA nanoparticles, respectively.     

Effects of Intestinal CYP3A4 and P-Glycoprotein on Oral Drug Absorption—Theoretical Approach

Purpose. To evaluate the effects of gut metabolism and efflux on drug absorption by simulation studies using a pharmacokinetic model involving diffusion in epithelial cells. Methods. A pharmacokinetic model for drug absorption was constructed including metabolism by CYP3A4 inside the epithelial cells, P-gp-mediated efflux into the lumen, intracellular diffusion from the luminal side to the basal side, and subsequent permeation through the basal membrane. Partial differential equations were solved to yield an equation for the fraction absorbed from gut to the blood. Effects of inhibition of CYP3A4 and/or P-gp on the fraction absorbed were simulated for a hypothetical substrate for both CYP3A4 and P-gp. Results. The fraction absorbed after oral administration was shown to increase following inhibition of P-gp. This increase was more marked when the efflux clearance of the drug was greater than the sum of the metabolic and absorption clearances and when the intracellular diffusion constant was small. Furthermore, it was demonstrated that the fraction absorbed was synergistically elevated by simultaneous inhibition of both CYP3A4 and P-gp. Conclusions. The analysis using our present diffusion model is expected to allow the prediction of in vivo intestinal drug absorption and related drug interactions from in vitro studies using human intestinal microsomes, gut epithelial cells, CYP3A4-expressed Caco-2 cells, etc.     

Penetration of garenoxacin into lung tissues and bone in subjects undergoing lung biopsy or resection

ABSTRACT

Objective: Concentrations of garenoxacin in plasma and samples of lung parenchyma, bronchial mucosa, and bone were determined following single-dose administration.

Research design and methods: Open-label, non-randomized study in which subjects undergoing invasive lung biopsy or resection were given a single 600?mg oral dose of garenoxacin. Lung parenchyma, and, if possible, bronchial mucosa and bone (i.e., flat bone with sinus mucosa or long bone from the lower legs) samples and corresponding plasma samples were obtained 2–4, 4–6, 10–12, or 20–24?h post-dose. Garenoxacin concentrations were measured using validated liquid chromatography with dual mass spectrometry. Safety was also assessed.

Results: Twenty-seven subjects enrolled and completed the study. Garenoxacin plasma concentrations (mean ± standard deviation) during the 24?h period ranged from 1.9 ± 1 to 7.4 ±3?µg/mL. Garenoxacin concentrations in lung tissue (15.2 ± 9?µg/g) peaked at 4–6?h and decreased to 3.7 ± 3?µg/g at 20–24?h. Mean ratios between bronchial mucosa and plasma ranged from 0.82 to 0.99 over a 24-h period. At 12?h, the mean ratio between bone and plasma was 0.56. Garenoxacin concentrations in lung tissue exceeded the MIC₉₀ for common respiratory pathogens by at least 61-fold. Garenoxacin was safe and well tolerated. Forty-five adverse events were reported by 26 subjects; none were determined to be attributable to garenoxacin by the investigators. Most of the adverse events were mild to moderate in severity.

Conclusions: Garenoxacin achieved 24-h concentrations in pulmonary tissues that exceeded the MIC₉₀ for common respiratory pathogens. A controlled study involving a larger number of lung and bone tissue samples is needed to further confirm these findings.     

Relative bioavailability of two oral formulations of navelbine in cancer patients

A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two-way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (C_max) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0–∞) AUC.     

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients

Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml^–1, C_max was 832 vs 871 ng⋅ml^–1 and t_max was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely. Received: 19 October 1995/Accepted in revised form: 8 January 1996     

Bioavailability and disposition kinetics of HI-6 in Beagle dogs

The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg^?1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A twocompartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (V_ss 203 ml kg^?1) and the drug was eliminated rapidly after intravenous administration (t_1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min^?1 × kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t_1/2(a), 5.3 min), MAT (17.1 min), C_max (70.37 μg ml^?1) and t_max (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t_1/2(a) (41.5 min), MAT (81.6 min), C_max (4.30 μg ml^?1) and T_max (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p <0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.     

Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo

Aerolized cyclosporine A (CsA) has been successfully used for prevention of organ rejection in lung transplant recipients. Various formulations of CsA are available and so far no direct comparison of their pharmacokinetics has been performed. Since clinical studies are elaborate, we sought a way to predict the kinetic behaviour of a propylene glycol solution of CsA (CsA-PG) and a liposomal formulation (L-CsA). The permeability across the human bronchial cell line Calu-3 revealed low permeability for CsA with the apparent permeability for CsA-PG being twice as high as for L-CsA. Employing a previously described dialysis model, the diffusion of CsA from human lung tissue into human blood was determined ex vivo. Consistent with the cell culture model results, we observed that the degree and rate of drug transfer into human blood was more pronounced for CsA-PG than for L-CsA with the area under the curve (AUC) of CsA-PG being about 1.6 times higher than for the L-CsA formulation. The diffusion rate was more than 50% higher from CsA-PG than from the liposomes. To conclude, both model systems consistently revealed that L-CsA displayed clearly a prolonged release effect and favourable longer tissue retention than CsA-PG.     

Dose-adjusted cyclosporine c2 in a patient with jejunoileal bypass as compared to seven other liver transplant recipients

Jejunoileal bypass (JIB) is a weight loss procedure in which malabsorption is produced by connecting a short length of proximal jejunum to the distal ileum. Because 90% of the small intestine is bypassed, it may have impact on the dose-concentration response of oral cyclosporine (CsA). The authors characterized the dose-adjusted blood concentrations of CsA obtained 2 hours (C2) after oral microemulsion CsA (ME-CsA) in a liver transplant (LTx) subject with an intact JIB, as compared with those from seven LTx controls without JIB. The biliary reconstruction involved choledochocholedochostomy without external drainage in all patients. ME-CsA was administered via a nasogastric tube within 24 hours after graft reperfusion. Oral fluconazole was given prophylactically to the study subject only for 6 days after LTx. During the first week after LTx, the dose-adjusted C2 (mean +/- SD) for the study subject and for controls was 53 +/- 10 and 106 +/- 47 ng/mL, respectively (P < 0.001). The corresponding value during the period from day 7 to day 107 was 105 +/- 40 and 257 +/- 86 ng/mL, respectively (P < 0.001). Multiple linear regression revealed that dosage, days after LTx, and the presence of a JIB were all independent predictors of C2 (R2 = 0.798, P = 0.037). Lack of bile resulting in malabsorption of ME-CsA was not thought to be significant contributor to her low dose-adjusted C2 because there was no external bile drainage and a portion of terminal ileum, where most bile acid reabsorption occurred, was still available after JIB. The fact that fluconazole failed to increase the dose-adjusted C2 in the study subject supports that enteric clearance of CsA may become clinically unimportant after JIB. Therefore, the low dose-adjusted C2 is most likely explained by the reduced bowel length and associated absorptive surface area after JIB. In conclusion, patients with JIB may require higher doses of ME-CsA.     

Reduced Systemic Availability of an Antiarrhythmic Drug,Bidisomide, with Meal Co-administration: Relationship with Region-Dependent Intestinal Absorption

Purpose. The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. Methods. Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. Results. Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (–13%) was substantially smaller than the reduction (from –43% to –63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 ± 5.7% and 23.7 ± 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased C_max but not AUC, while viscous homogenized solid meals decreased both C_max and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. Conclusions. The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.     

Long-lasting inhibition of the intestinal absorption of fexofenadine by cyclosporin A in rats

The purpose of the present study is to examine the long-lasting inhibition of intestinal organic anion transporting polypeptides (Oatps) by cyclosporin A (CsA) in rats using fexofenadine (FEX) as a probe drug. We examined the pharmacokinetics of FEX after its intravenous or oral administration to rats at 3 or 24 h after the oral administration of CsA. When FEX was administered at 3 h after the administration of CsA, its plasma concentration increased regardless of whether it was administered intravenously or orally. When FEX was intravenously administered at 24 h after the oral administration of CsA, its plasma concentration was increased; however, that observed after its oral administration was not significantly different from the vehicle-treated control. When FEX was administered at 3 h after the administration of CsA, the hepatic availability (F(h)) and the fraction absorbed in the intestine as an unchanged form (F(a)·F(g)) of FEX were increased, resulting in increased bioavailability (=F(a)·F(g)·F(h)). At 24 h after the administration of CsA, the F(h) of FEX was increased, whereas its bioavailability was decreased, suggesting that its F(a)·F(g) was decreased because of the long-lasting inhibition. In conclusion, CsA has long-lasting inhibitory effects on Oatps in the rat intestine as well as in the liver.     

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size. The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSA_d) (r² = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSA_d 60 ² while drugs that are < 10% absorbed had a PSA_d > 140 ². Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.     

非线性混合效应模型法计算1型糖尿病大鼠环孢素药代动力学参数

目的 研究糖尿病对环孢素(Ciclosporin, CsA)体内药物代谢动力学的影响。方法 大鼠腹腔注射65 mg·kg^-1链脲菌素(STZ)建立1型糖尿病大鼠模型。造模5周后通过荧光偏振免疫分析(FPIA)法检测大鼠灌胃环孢素(10 mg·kg^-1)后全血中的环孢素浓度,采用非线性混合效应法(Nonlinear mixed effect model, NONMEM)建立药物代谢动力学模型,贝叶斯(Bayes)反馈法获取个体参数并比较。结果 STZ注射1周后,大鼠空腹血糖超过11.1 mmol·L^-1,确认1型糖尿病大鼠造模成功。造模5周后,糖尿病大鼠的血糖显著增高。给药后,环孢素在大鼠体内呈现一房室模型,群体典型值及个体间差异(Between Subject Variability, BSV)分别为：CL/F=0.525 L·h^-1, BSV=32.1%;V/F=5.18 L, BSV=35.6%; Ka=1.82,BSV= 71.1%。正常组与糖尿病组大鼠CL/F无显著性差异(P>0.05);V/F无显著性差异(P>0.05);Ka有显著性差异(P<0.05) 。结论 1型糖尿病大鼠灌胃环孢素的吸收速率常数显著改变,且存在较大的个体间差异,提示糖尿病状态下会影响环孢素的吸收。     

Role of cytochrome P4502D6 in the metabolism of brofaromine

Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period.The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t_1/2, t_max and C_max were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml^–1 versus 223 ng · ml^–1. This, together with a significantly longer t_1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA.In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime.It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.     

TIME-DEPENDENT CYCLOSPORINE A-INDUCED NEPHROTOXICITY IN RATS

1. We investigated the toxicity of cyclosporine A (CsA) with reference to the timing of its administration in rats. 2. To elucidate the time-dependent effects of CsA on renal function and survival rate, CsA (75 mg/kg per day) or vehicle was orally administered once daily at four different times (3,9, 15 and 21 h after lights on; HALO) over a period of 21 days to male Wistar rats (n= 56) kept in rooms with a 12 h light-dark cycle. 3. On the 7th day after treatment, creatinine clearances (Ccr) of groups dosed at 3 and 9 HALO (inactive period) were not reduced in comparison with clearances of time-matched control rats, whereas Ccr significantly decreased in rats dosed at 15 and 21 HALO (active period). Cyclosporine A markedly increased urinary N-acetyl-β-D-glucosaminidase (NAG) excretion in all dosed groups at the 7th day after treatment, except for rats dosed at 3 HALO. In rats dosed at 3 HALO, Ccr decreased progressively; however, it did not decrease progressively in rats dosed at 9 HALO. In surviving rats treated during the inactive period, urine NAG subsequently returned to control levels. Survival rates were greater in animals dosed during inactive periods than those in groups dosed during active periods. 4. Significant differences in CsA-induced toxicity were obvious as a result of the timing of its administration. A different time course between Ccr and urine NAG excretion was observed during repeated CsA administration. Degenerative changes in proximal tubules were demonstrated after chronic administration of CsA, suggesting that severe and persistent tubular damage cannot be assessed by urinary NAG excretion.     

The Fate of Phenglutarimide Hydrochloride in the Rat and Man

Abstract

1. In the rat, [¹⁴C]phenglutarimide HCl was completely absorbed from the gastrointestinal tract and totally excreted in the urine within 24 h after dosing. The drug was not metabolized.

2. [¹⁴C]Phenglutarimide was widely distributed throughout the body of the rat but only very low levels of radioactivity were detected in the brain. In pregnant animals the drug traversed the placenta and radioactivity was detected in the foetus and amniotic fluid in concentrations higher than or similar to those in the maternal plasma.

3. On absorption from the gastrointestinal tract, the drug was rapidly excreted into the urine and consequently tissue levels were low.

4. In man, after oral administration of non-radioactive phenglutarimide, the drug was excreted completely in the urine as the unchanged compound within 24 h after dosing.

5. In mice, phenglutarimide inhibited the peripheral but not the central actions of oxotremorine, an observation in accord with the distribution pattern of the drug in the rat.

6. Phenglutarimide inhibited the response of the isolated guinea-pig bladder to coaxial stimulation. It is suggested that sufficiently high concentrations of phenglutarimide may be reached in the bladder in vivo to inhibit the bladder reflex in man.     

Penetration of Cefaclor Into the Interstitial Space Fluid of Skeletal Muscle and Lung Tissue in Rats

Purpose. To measure and compare the penetration of cefaclor from the plasma compartment into the interstitial space of lung and skeletal muscle in rats and to integrate the data in a pharmacokinetic model. Methods. Unbound interstitial concentrations in muscle and lung were measured by in vivo microdialysis following i.v. bolus doses of 50 and 75 mg/kg cefaclor. Unbound muscle concentrations were also measured after a primed, continuous i.v. infusion at an infusion rate of 0.3 mg/kg/min. Results. The cefaclor half-life in plasma, muscle and lung was approximately 1 h. Unbound cefaclor concentrations in muscle and lung were found to be virtually identical. A 2-compartment body model was fitted to the data with a tissue penetration factor (AUC_{tissue(unbound)}/AUC_{plasma(unbound)}) of approximately 0.26 independent of dose, tissue and mode of administration. Conclusions. Unbound concentrations of cefaclor in the interstitial space fluid of lung and skeletal muscle are of similar magnitude and lower than those in plasma. Using total plasma concentrations would overestimate the antibacterial activity of the drug and therefore its clinical efficacy. Instead, therapeutically active levels of cefaclor at the site of action should be taken into account. Microdialysis allows direct measurement of these unbound concentrations.     

Correlation Between sPLA2-llA and Phosgene-Induced Rat Acute Lung Injury

Secreted phospholipase A₂ of group IIA (sPLA₂-IIA) has been involved in a variety of inflammatory diseases, including acute lung injury. However, the specific role of sPLA₂-IIA in phosgene-induced acute lung injury remains unidentified. The aim of the present study was to investigate the correlation between sPLA₂-IIA activity and the severity of phosgene-induced acute lung injury. Adult male rats were randomly exposed to either normal room air (control group) or a concentration of 400 ppm phosgene (phosgene-exposed group) for there are 5 phosgene-exposed groups altogether. For the time points of 1, 3, 6, 12 and 24 h post-exposure, one phosgene-exposed group was sacrificed at each time point. The severity of acute lung injury was assessed by Pa_O2/F_IO2 ratio, wet-to-dry lung-weight ratio, and bronchoalveolar lavage (BAL) fluid protein concentration. sPLA₂-IIA activity in BAL fluid markedly increased between 1 h and 12 h after phosgene exposure, and reached its highest level at 6 h. Moreover, the trend of this elevation correlated well with the severity of lung injury. These results indicate that sPLA₂-IIA probably participates in phosgene-induced acute lung injury.