Ultrasound-guided repositioning technique for partially expelled intrauterine device: descriptive feasibility study.

OBJECTIVE: To describe the feasibility of an ultrasound-guided repositioning technique for partially expelled intrauterine devices (IUDs) without use of sedation. METHODS: This was a descriptive feasibility study of patients with a partially expelled IUD managed in our outpatient clinic from January 2016 to February 2020. The partially expelled IUDs (vertical arm extending partially or entirely through the cervical canal) were repositioned at the uterine fundus using Hartmann alligator forceps under ultrasound guidance. Paracervical or intracervical anesthesia and prophylactic antibiotics were not used. Data related to the procedure and 6-month follow-up were extracted from patient medical records. The primary outcome was the success rate of the repositioning procedure, defined as ultrasound confirmation of the entire IUD located above the internal os. Secondary outcomes included the retention and expulsion rates of the repositioned IUD at 6 months after the procedure and description of complications. RESULTS: We included data from 55 women with a partially expelled IUD (35 levonorgestrel IUDs and 20 copper IUDs) referred for repositioning. Ultrasound-guided repositioning of the IUD was successful in 51 (92.7%) cases, while the procedure was not completed in four patients due to pain. Of the 55 procedures, 48 (87.3%) were performed by obstetrics and gynecology trainees under the supervision of a senior specialist. Among the 51 successfully repositioned IUDs, nine (17.6%) were expelled within 6 months after the procedure and six patients were lost to follow-up. No uterine perforation or infection-related complications occurred within 6 months of the procedure. CONCLUSION: The ultrasound-guided repositioning technique appears to be a safe and feasible approach for partially expelled IUDs. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Clomiphene citrate and letrozole to reduce follicle-stimulating hormone consumption during ovarian stimulation: systematic review and meta-analysis.

OBJECTIVE: To assess the available evidence comparing effectiveness of ovarian stimulation (OS) using clomiphene citrate (CC) and/or letrozole (LTZ) to reduce follicle-stimulating hormone (FSH) consumption compared with standard OS. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials that compared reproductive outcomes following in-vitro fertilization. We searched 11 electronic databases and hand-searched the reference lists of included studies and related reviews. We stratified the results, separating studies according to the oral agent used (CC or LTZ) and the characteristics of the included women (expected poor ovarian response or other women). When combining the results of the included studies, we assessed the relative risk (RR) for live birth, clinical pregnancy, miscarriage and cycle cancelation, the Peto odds ratio (OR) for ovarian hyperstimulation syndrome (OHSS) and mean difference (MD) for the number of oocytes retrieved and FSH consumption. RESULTS: A total of 22 studies were included in the review. Considering women with expected poor ovarian response, the available evidence suggested that using CC to reduce FSH consumption during OS provided similar rates of live birth (RR, 0.9 (95% CI, 0.6-1.2), moderate-quality evidence) and clinical pregnancy (RR, 1.0 (95% CI, 0.8-1.4), moderate-quality evidence); the use of LTZ did not cause a relevant change in the number of oocytes retrieved (MD, -0.4 (95% CI, -0.9 to 0.1), high-quality evidence). Considering the studies evaluating other women, the available evidence suggested that using CC to reduce FSH consumption during OS reduced the number of oocytes retrieved (MD, -4.6 (95% CI, -6.1 to -3.0), high-quality evidence) and risk of OHSS (Peto OR, 0.2 (95% CI, 0.1-0.3), moderate-quality evidence), while results were similar for rates of live birth (RR, 0.9 (95% CI, 0.7-1.1), moderate-quality evidence) and clinical pregnancy (RR, 1.0 (95% CI, 0.8-1.1), high-quality evidence). The quality of the evidence was low or very low for other outcomes. CONCLUSION: The use of CC to reduce FSH consumption in women with expected poor ovarian response has the advantage of providing similar reproductive outcomes with reduced costs. For the other women, the use of CC for reducing FSH consumption has the additional advantage of reducing OHSS, but also reduces the total number of oocytes retrieved. More studies are needed to evaluate the effect of LTZ for the same purpose. Future studies should focus on cumulative pregnancy per oocyte retrieval, patient dissatisfaction and agreement to repeat the cycle if not pregnant, which are important outcomes for clinical decisions. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Tubulointerstitial injury induced in rats by a monoclonal antibody that inhibits function of a membrane inhibitor of complement.

The kidney widely expresses membrane-associated complement regulatory proteins (membrane inhibitors of complement). The aim of this work was to evaluate the roles of these molecules in rat kidneys in vivo. To suppress functions of rat membrane inhibitors of complement, two mAbs, 512 and 6D1, were used. 5I2 and 6D1 inhibit functions of membrane inhibitors of complement at C3 level (rat Crry/p65) and C8/9 level (rat CD59), respectively. F(ab')2 fragment of 5I2 or 6D1 was perfused in the left kidneys, and perfusate was discarded from the renal vein. After perfusion, the left kidneys were connected to systemic circulation. In rats perfused with 5I2, mouse IgG was found in glomeruli, peritubular capillaries, vascular bundles, and tubules 15 min after recirculation. Binding of C3 and C5b-9 was evident in these areas. 1 d after perfusion with 5I2, cast formation, dilatation of tubular lumen, and tubular cell degeneration were observed. At day 4 through day 7, significant mononuclear cell infiltration and proximal tubule damage were observed. These changes were completely prevented by complement depletion. Rats perfused with 6D1 showed the binding of mouse IgG in the similar areas as 5I2, but C3 or C5b-9 deposition was not observed. Rats perfused with 6D1 or vehicle only did not show any pathology in the left kidneys. These results suggest that rat Crry/p65 plays protective roles against spontaneously occurring indiscriminate attack to tubulointerstitial tissues by autologous complement and that rat Crry/p65 is one of the important factors to maintain normal integrity of the kidney in rats.

A red-NIR fluorescent dye detecting nuclear DNA G-quadruplexes: in vitro analysis and cell imaging.

Aggregation, red-NIR emission and light-up upon nucleic acid G-quadruplex binding have been investigated for a prototype core-extended naphthalene diimide, which is capable of fast cellular entry and nucleolar localization. Both high-level colocalization with an anti-G-quadruplex antibody and nucleolin displacement reveal that the compound targets and thus makes visible nuclear DNA G-quadruplexes.

In vitro basis for schedule-dependent interaction between gemcitabine and topoisomerase-targeted drugs in the treatment of colorectal cancer.

BACKGROUND: While combination of gemcitabine with anti-topoisomerase poisons is routinely used in oncology, little is known on the biological interactions between these drugs. DESIGN: To understand the cellular basis for this association, we hypothesized an interaction of the two agents at the topoisomerase level. A real-time RT-PCR method was designed to quantify topoisomerase expression after treatment with gemcitabine (GEM) in two human colon adenocarcinoma cell lines. Efficacy of drugs as single agents and in combination was analyzed on the basis of their cytotoxic effects. RESULTS: We showed that a) gemcitabine induces expression of all major eukaryotic topoisomerases (I, II alpha and beta) at definite times after drug administration; b) cytotoxicity was more relevant when cells were treated with GEM and the topoisomerase poison within a short period of time. In particular synergistic effects were found when the anti-topoisomerase II agent was given 3 h after gemcitabine or when the anti-topoisomerase I drug was delivered 3 h before or after the antimetabolite. CONCLUSIONS: These findings help explaining the effectiveness of the combined therapy GEM/topoisomerase poisons and suggest a drug administration protocol for clinical treatment.

Topoisomerase I, II alpha and II beta mRNA expression in peripheral blood mononuclear cells of patients with solid tumor: preliminary results.

BACKGROUND: The pyrimidine antimetabolite Gemcitabine (G) (2',2'-difluorodeoxycytidine) is used against several malignancies G exerts its antitumour effect mainly by incorporation of its triphosphate metabolite (dFdCTP) into DNA. Subsequently, DNA polymerase adds one additional deoxynucleotide and DNA synthesis is interrupted. The nuclear enzymes topoisomerase I and II (TPs) are critical for DNA function and cell survival; they control, maintain and modify DNA topology during both replication and translation of genetic materials. These enzymes induce cuts in one or both strands of DNA, allowing strands to pass through the nick and then rejoining the nicked strand of DNA. Anti-topoisomerase (TPs-inhibitors) drugs exist and are largely used in chemotherapy, however, most often blindly of the cancer TPs status. AIM: To understand the best association between G and TPs-inhibitors, we studied: (a) Topoisomerases I, II alpha and II beta mRNA expression in Peripheral Mononuclear Blood Cells (PBMCs) of patients with solid tumor, after 1, 2, 3, 4, 5, 6 h after treatment with Gemcitabine (G); b) in vivo expression of TPs genes after administration of Gemcitabine (a topoisomerases up-regulating drug) combined with the TPs inhibitors drugs (TID) Topotecan (T) and Etoposide (E), added to the culture beneath 1 h after TPD treatment. TPs mRNA expression was measured by quantitative real-time RT-PCR in PBMCs. RESULTS: The administration of 1-h infused G is followed by a fast rise of TPs expression (P > 0.0001 Student's t test, paired data, each patient control of himself); TPs inhibitors, sequentially given after G, highly reduced the TPs rising (P > 0.0001). CONCLUSIONS: G induces a TPs increase. A rationale might be available for combination chemotherapy (G plus TPs inhibitors). The study is ongoing to enroll further patients.

Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats.

The effect of endotoxin on glucuronidation and hepatobiliary transport of quinolone antimicrobial agents was investigated in rats using sparfloxacin and p-nitrophenyl glucuronide as model drugs. The biliary clearance experiments were performed 24 h after a single intraperitoneal injection of endotoxin (1 mg/kg). Endotoxin significantly delayed the disappearance of sparfloxacin from plasma and increased plasma concentration of its glucuronide after intravenous injection of sparfloxacin (10 mg/kg). Significant decreases in the systemic clearance of sparfloxacin and the biliary clearance of sparfloxacin and the glucuronide were observed. Endotoxin had no effect on in vitro glucuronidation activity using p-nitrophenol as a substrate. When p-nitrophenyl glucuronide (8 mg/kg) was administered in endotoxin-pretreated rats, significant decreases in the systemic clearance, biliary clearance and renal clearance of p-nitrophenyl glucuronide were observed. These findings suggest that endotoxin decreases the biliary excretion of sparfloxacin and its glucuronide probably due to impairment of their hepatobiliary transport systems and renal handling.

Carbapenem-induced endotoxin release in gram-negative bacterial sepsis rat models.

The carbapenem-induced endotoxin release was evaluated using experimental models of gram-negative bacterial sepsis in Wistar rats. Infections with Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris and Proteus mirabilis resulted in an increase of the plasma endotoxin concentration after treatment with ceftazidime and carbapenems including imipenem, panipenem, meropenem and biapenem. Except for P. aeruginosa, the plasma endotoxin concentrations after carbapenem treatment were significantly lower than those after ceftazidime treatment. It is noteworthy that treatment of P. aeruginosa sepsis with meropenem or biapenem induced significantly more endotoxin release than other carbapenems and the endotoxin concentrations induced by these carbapenems reached those of ceftazidime treatment. The plasma endotoxin concentrations appeared to correlate with the reduction of platelet counts and the elevation of both glutamic oxaloacetic transaminase and glutamic pyruvic transaminase values.

Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline.

The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose-independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single-injection renal clearance method, were 21.25 micrograms/mL for the Michaelis-Menten constant and 102.38 micrograms/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady-state volume of distribution of DPP. The effect of probenecid concentration on the steady-state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid-insensitive transport systems for DPP in the renal proximal tubule. The Michaelis-Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 micrograms/mL.

Protein binding of xanthine derivatives to guinea pig serum albumin.

Binding of the bronchodilators N3-alkylxanthine and N3-alkyl-N1-methylxanthine derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of xanthine derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of xanthine derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylxanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of xanthine derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each xanthine derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among xanthine derivatives is related to hydrophobicity, which is an important determinant of their biological activities.

Dose-dependent pharmacokinetics of enprofylline and its renal handling in rats.

The effect of dosage on the pharmacokinetics of the potent bronchodilator enprofylline (3-propylxanthine; PX) and its renal handling were investigated in rats. Enprofylline (PX) was administered iv in dosages of 2.5, 10, 20, and 40 mg/kg, and PX concentration in plasma and urine was determined by HPLC. The pharmacokinetic parameters were estimated by model-independent methods. The disappearance of PX from plasma was delayed as dosage was increased. The corresponding pharmacokinetic parameters also showed dose dependency; increases in the volume of distribution (Vd) and mean residence time (MRT) and a decrease in total body clearance (CLT) were observed as dosage was increased from 2.5 to 40 mg/kg. Approximately 80% of the dose, however, was excreted in urine as unchanged PX. Plasma protein binding studies of PX showed concentration dependency and allowed determination of binding parameters, with an apparent dissociation constant (Kd) of 162.50 microM and a binding capacity (nP) of 565.23 microM. Some pharmacokinetic parameters for unbound PX calculated by total plasma concentration and binding parameters also showed dose-dependent characteristics. However, no significant change in Vd for unbound PX was observed among administered doses, indicating that the distribution of PX into the body tissues is not changed by an increase in dosage. Renal clearance of unbound PX significantly increased as plasma concentration decreased. The maximum transport capacity (Vmax) and the Michaelis-Menten constant (Km) for tubular secretion were 60.53 micrograms/min and 2.27 micrograms/mL, respectively. The aim of the present study is to demonstrate that both saturable tubular secretion and concentration-dependent protein binding are responsible for the dose-dependent pharmacokinetics of PX in rats.

Pharmacokinetic characteristics of N7-substituted theophylline derivatives and their interaction with quinolone in rats.

Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CLT) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 L/h/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal clearance (CLR) was 1.75 L/h/kg, approximately 13-fold the CLR for PXP (0.13 L/h/kg) and sevenfold the rat glomerular filtration rate. This study indicates that in rats, DPP is mainly excreted by active tubular secretion and that renal tubular reabsorption contributes to renal excretion of PXP with glomerular filtration. No significant changes in any pharmacokinetic parameters of the two drugs were observed when they were coadministered with enoxacin, compared with the drug administered alone, suggesting that enoxacin had no effect on the pharmacokinetics of either drug.

Lincomycin-induced endotoxin release in Escherichia coli sepsis: evidence for release in vitro and in vivo.

OBJECTIVE: To evaluate the propensity of lincomycin and clindamycin to induce release of endotoxin, the authors investigated endotoxin release in Escherichia coli isolated from a patient who developed septic shock following lincomycin treatment. METHODS: Endotoxin release from the E. coli isolate exposed to lincomycin, clindamycin, and ceftazidime were determined in vitro and in vivo. RESULTS: In vitro, this E. coli released significantly larger amounts of endotoxin after exposure for 6 hours to lincomycin or clindamycin versus no antibiotic; however, endotoxin release with these antibiotics was significantly less than with ceftazidime. There was no significant difference in in vitro endotoxin release between small (8 mg/L) and large (0.5 minimum inhibitory concentration [MIC]) doses of these antibiotics, and 0.5 MICs of lincomycin and clindamycin were 1024 and 256 mg/L, respectively. These results were supported by scanning electron microscopic observations, which demonstrated that lincomycin, clindamycin, and ceftazidime induced formation of filamentous cells. In addition, plasma endotoxin concentrations after treatment for 4 hours with lincomycin, clindamycin, and ceftazidime (5 mg/kg) were at least 20-fold higher than with no antibiotic in an E. coli sepsis rat model. CONCLUSION: Results of this study suggest that the bacteriostatic antibiotics, lincomycin and clindamycin, induce endotoxin release in the treatment of E. coli infections.

Lack of effect of Chinese medicines on bioavailability of ofloxacin in healthy volunteers.

Recently, Chinese medicines have become available as OTC drugs and are frequently prescribed with Western medicine for the treatment of various chronic diseases. In this study, the effect of the Chinese medicines Sho-saiko-to (TJ-9), Rikkunshi-to (TJ-43) and Sairei-to (TJ-114) on the bioavailability of ofloxacin (OFLX) was investigated in seven volunteers in an open, random crossover fashion. Subjects received a single oral dose of OFLX (200 mg) alone and with coadministrations of each Chinese medicine, at one-week intervals. Plasma and urine samples were analyzed by high-performance liquid chromatography. No significant differences in any estimated bioavailability parameters of OFLX were observed between the two phases. The urinary recovery of OFLX excreted within 24 h after the administration of OFLX alone, 80.6 +/- 3.9% (mean +/- SEM), was not significantly different from those after the coadministrations of the Chinese medicines (79.7 +/- 5.1% for TJ-9, 76.8 +/- 2.3% for TJ-43 and 80.3 +/- 5.3% for TJ-114), suggesting that there was no difference in the systemic availability of the four doses. These findings indicate that the Chinese medicines studied have no significant effect on the rate and extent of bioavailability of OFLX.

The effects of N-benzoyl-beta-alanine, a new nephroprotective drug, on the distribution and renal excretion of enprofylline in rats.

The effects of the new nephroprotective drug N-benzoyl-beta-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2.5 mg kg-1 under three different steady-state plasma BA concentrations (100, 200 and 400 micrograms mL-1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 micrograms mL-1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 micrograms mL-1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.

Structure-pharmacokinetic relationships among the N1,N3-alkylxanthines in rats.

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1,N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P less than 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.

Interspecies differences and scaling for the pharmacokinetics of xanthine derivatives.

Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1-methyl-3-propylxanthine (MPX), were investigated in mice, rats, guinea-pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model-independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non-renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals.

Influence of age on the disposition and renal handling of enprofylline in rats.

The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (Vmax)(223.33, 160.24 and 142.98 micrograms min-1 kg-1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (Vmax/Km) of enprofylline (75.45, 51.03 and 44.13 mL min-1 kg-1, respectively), while a slight change in the Michaelis-Menten constant (Km) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.

The effect of lipopolysaccharide on the disposition of xanthines in rats.

The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0.25 mg kg-1 over a period of 20-30 min, 2 h before the administration of theophylline (10 mg kg-1) or MPX (2.5 mg kg-1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.