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Intranasal corticosteroid therapy has exhibited effectiveness for improving nasal symptoms and quality of life (QOL) scores associated with seasonal allergic rhinitis. We prospectively investigated the efficacy of mometasone furoate nasal spray (MFNS) for improving the total nasal symptom score, QOL score, and sleep quality in subjects with perennial allergic rhinitis (PAR). Nasal airway conditions were also objectively assessed by measuring nasal nitric oxide (NO). Fifty-seven patients with PAR were randomized to MFNS or placebo for a 14-day, double-blind, crossover study. The subjects recorded their symptoms on nasal symptom forms and a visual analog scale. QOL and sleep quality were surveyed in accordance with the Japanese version of the Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) and the Japanese version of the Epworth Sleepiness Scale. Nasal NO was measured during a single exhalation using a chemiluminescence analyzer. MFNS treatment achieved significant reductions versus placebo for total nasal symptoms (p < 0.001). There were significant decreases of the usual daily activity domain (p < 0.005), outdoor activities (p < 0.01), social function (p < 0.05), and the overall QOL score (p < 0.05) of JRQLQ with MFNS therapy versus placebo. A significant reduction of the sleepiness scale was also observed in the MFNS group with high sleep disturbance (p < 0.01). A significant decrease of nasal NO was found in the MFNS group (p < 0.01), especially among patients with severe nasal symptoms (p < 0.005). This prospective study indicated that MFNS therapy significantly improves nasal symptoms, QOL, sleep quality, and upper airway condition in Japanese subjects with PAR.

Aim St John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined. Methods Thirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day−1) or placebo for 14 days. The study was performed in a randomized, placebo-controlled, cross-over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14. Results SJW decreased the plasma quazepam concentration. The Cmax and AUC0-48 of quazepam after SJW were significantly lower than those after placebo [Cmax; −8.7 ng ml−1 (95% confidence interval (CI) −17.1 to −0.2), AUC0-48; −55 ng h ml−1 (95% CI −96 to −15)]. The urinary ratio of 6β-hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85–3.4)). Quazepam, but not SJW, produced sedative-like effects in the VAS test (drowsiness; P

In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and mu opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.

Hospital-acquired bloodstream infections (BSIs) are significant causes of mortality, and strategies to improve outcomes are needed. We aimed to evaluate the clinical efficacy of a multidisciplinary infection control team (ICT) approach to the initial treatment of patients with hospital-acquired BSI.A before-after quasiexperimental study of patients with hospital-acquired BSI was performed in a Japanese university hospital. The ICT provided immediate recommendations to the attending physician about appropriate antimicrobial therapy and management after reviewing blood cultures, Gram's stain, final organism, and antimicrobial susceptibility results.The sample included 469 patients with hospital-acquired BSI (n = 210, preintervention group; n = 259, postintervention group). There were no significant differences between the groups in background or microbiologic characteristics. The 30-day mortality was significantly lower and significantly more patients received appropriate antimicrobial therapy in the postintervention group (22.9% vs 14.3%; P = .02 and 86.5% vs 69.0%; P.001, respectively). Multivariate analysis confirmed that the ICT intervention was significantly associated with appropriate antimicrobial therapy (odds ratio, 2.22; 95% confidence interval, 1.27-3.89) and 30-day mortality (odds ratio, 0.49; 95% confidence interval, 0.25-0.95).A timely multidisciplinary team approach decreases the delay of appropriate antimicrobial treatment and may improve HABSI patient outcomes.

Objective St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study. Methods Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug. Results Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P < .05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P < .05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials. Conclusions This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver. Clinical Pharmacology & Therapeutics (2001) 70, 518–524; doi: 10.1016/S0009-9236(01)64092-X

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

A new prediction method of vancomycin (VCM) pharmacokinetics has been developed using the modified Bayesian forecasting method involved in time-dependent pharmacokinetics in clearance. We investigated to evaluate the usefulness of this new prediction method compared with that of the ordinary Bayesian forecasting method. Serum samples, obtained from 4 patients at least 3 different days during the period for the VCM treatment were assayed by fluorescence polarization immunoassay. VCM pharmacokinetic parameters and predicted serum VCM concentrations were calculated using this new method and the ordinary one according to the one-compartment model. The precision of the predicted serum VCM concentrations by these two methods at the third experimental day were evaluated with the mean prediction error (ME), mean absolute prediction error (MAE) and root mean squared error (RMSE). The most precise and least-bias prediction of serum VCM concentrations were observed using this new prediction method (ME: -0.36 +/- 1.40, MAE: 1.13 +/- 0.82 and RSME: 1.37). The time-dependent decrease of VCM clearance was observed in all patients. Therefore, the fitting of the actual serum VCM concentrations obtained using the ordinary method produced less precise results than that using this new method. These results suggest the usefulness of this new prediction method considering time-dependent changes in VCM clearance.

Cysteinyl leukotriene and leukotriene receptor occupancy have been linked to several processes in seasonal allergic rhinitis (SAR), including nasal congestion, rhinorrhea, and recruitment of inflammatory cells. We investigated whether add-on loratadine, an antihistamine, might be effective for SAR patients showing unsatisfactory control of symptoms with the leukotriene receptor antagonist (LTRA) montelukast alone. Patients with SAR caused by Japanese cedar pollen (SAR-JCP; mean age, 29.4 years) were given prophylactic montelukast for 1 month before peak JCP dispersal. Patients recorded the severity of the symptoms (sneezing, rhinorrhea, nasal congestion, and ocular symptoms) daily on visual analog scale (VAS). We selected patients with VAS scores of >50 for any of the symptoms just before the peak pollen season (March 2 to March 8) and designated them as "poorly controlled" patients. Then, in the peak JCP season (from March 9), we conducted a randomized, double-blind, placebo-controlled study to determine whether add-on loratadine might be effective for these "poorly controlled" patients. Montelukast alone was effective, as evaluated by improvement of the VAS scores, in 95 of the 137 patients (69.3%). Add-on loratadine significantly decreased the total scores for nasal symptoms (p < 0.05), sneezing (p < 0.05), and rhinorrhea (p < 0.05) when compared with placebo. The symptoms of SAR in two of three SAR-JP patients could be controlled (VAS score[s] under 50) by prophylactic treatment with montelukast alone under the condition of mild JCP dispersal. Furthermore, the effect of add-on antihistamine on sneezing and rhinorrhea was found in selected SAR-JCP patients.

Granulocyte colony-stimulating factor administration is an important component of supportive therapy in chemotherapy-induced leukopenia. Although patient response to granulocyte colony-stimulating factor administration is known to vary, the factors responsible for poor response have not been identified.To identify the predictors of the responses of patients with solid tumors to granulocyte colony-stimulating factor.A 600-bed university hospital offering secondary and tertiary care in Japan.This retrospective cohort study examined the response of 181 patients with solid tumors who were administered prophylactic granulocyte colony-stimulating factor for the first time after they developed severe grade 3/4 leukopenia (white blood cell count2,000 × 10(-9)/L) because of adjuvant or neoadjuvant chemotherapy. The granulocyte colony-stimulating factor response was defined as the length of the leukocyte recovery period, which was assessed as the period within which the normal white blood cell count (white blood cell count3,000 × 10(-9)/L) is reached after the first dosage of granulocyte colony-stimulating factor. After classification of the patients as either poor or normal granulocyte colony-stimulating factor responders according to the confidence interval of the recovery period, their characteristics were compared.The time for recovery to normal white blood cell count was 2-7 days (90 % confidence interval), and the cutoff value for differentiating poor responders (n = 14) from normal responders (n = 167) was 8 days. Univariate analysis identified previous radiotherapy, number of chemotherapy courses, high granulocyte colony-stimulating factor dosage, and hypoalbuminemia to be significantly associated with granulocyte colony-stimulating factor response. Multivariate analysis identified undergoing four or more chemotherapy courses (odds ratio = 5.09; 95 % confidence interval, 1.14-22.71) and heart failure (odds ratio = 5.96; 95 % confidence interval, 1.09-32.57) to be significantly associated with poor granulocyte colony-stimulating factor response.Undergoing four or more chemotherapy courses and heart failure are independent risk factors for poor response to granulocyte colony-stimulating factor. These findings may help prevent the complications of leukopenia during chemotherapy and highlight the need to develop better strategies for preventing and treating infectious disease in patients undergoing granulocyte colony-stimulating factor administration.

Background: Myelotoxicity, a major toxicity of vinorelbine, may be related to the degree of one's exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbine's pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. To date, macrolide–vinorelbine drug interactions have not been reported. Objective: To estimate the clinical risk of a interaction between vinorelbine and clarithromycin. Methods: In a retrospective cohort study, we searched computerized medical records of patients who had been administered vinorelbine in the University of Fukui Hospital. The study cohort was defined as all patients with non–small-cell lung cancer who received vinorelbine between May 30, 2003, and January 31, 2008. The treatment courses were classified according to whether or not clarithromycin was concomitantly administered with vinorelbine. Nadir neutrophil counts were recorded as the major outcomes. Vinorelbine–clarithromycin interaction was defined as a significant increase in the risk of severe neutropenia when the 2 drugs were administered concomitantly. Results: A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively. Conclusions: Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

Effects of disodium ethylenediaminetetraacetate (EDTA) and bile salts on the ion-selective permeability and electrical resistance (Rm) of rat jejunal membrane were investigated in vitro to characterize the enhanced permeability to drugs by these adjuvants. Ion-selective permeability was estimated from diffusion potentials across the membrane and expressed as permeability ratios for ions (Pcl/PNa, PK/PNa). Pretreatment of the mucosal membrane with EDTA increased PCl/PNa and decreased Rm. At the same time, the mucosal-to-serosal flux rate of sulfanilic acid (SA), a model of polar drugs, was enhanced. The relationship between Pcl/PNa and SA flux rate after pretreatment with EDTA was demonstrated to yield a curve asymptotic to the free mobility ratio of those ions. When bile salts were used as the pretreatment agent, instead of EDTA, similar results to the case of EDTA were obtained. Assuming that EDTA interacts with the tight junctional portion of the mucosal membrane to enhance the paracellular permeability to drugs selectively, as demonstrated in many other reports, changes in PCl/PNa and Rm were assumed to correspond to structural change in the tight junction. Consequently, we suggest that these factors can be useful parameters when considering the mechanism of enhanced permeability of the intestinal membrane by several adjuvants.

The impact of lower serum albumin levels on teicoplanin pharmacokinetics has not been previously determined. The authors assessed the relationship between total and free concentrations of teicoplanin in serum samples obtained from patients receiving teicoplanin therapy for Gram-positive bacterial infections. In addition, the authors determined the contribution of serum albumin concentrations to the unbound fraction of teicoplanin. One hundred ninety-eight serum samples were obtained from 65 patients undergoing routine therapeutic drug monitoring of teicoplanin. Free serum teicoplanin was separated by ultrafiltration, and total and free serum concentrations of teicoplanin were determined by a fluorescence polarization immunoassay. Regression analysis was then performed to build a prediction model for the free serum teicoplanin concentration from the total serum teicoplanin concentration and the serum albumin level using the first 132 samples. The predictive performance of this model was then tested using the next 66 samples. Free serum teicoplanin concentrations (Cf) (mug/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (mug/mL) and albumin concentrations (ALB) (g/dL): Cf = Ct/(1 + 1.78 * ALB). This model could estimate free serum teicoplanin concentrations with a small bias and an acceptable error. The measured free level of teicoplanin will lie between 0.63 and 1.38 times the predicted concentration in 95% of cases. Serum albumin level plays a major role in the variability of the fraction unbound of teicoplanin. This model can reliably estimate free serum teicoplanin concentrations more easily than by using direct measurements.

We have developed a simple, sensitive and reliable assay procedure for cyclosporin A (CyA), a modified fluorescence polarization immunoasay method incorporating fat emulsion (FE-FPIA), to determine the CyA content in rat skin. The conventional fluorescence polarization immunoassay (FPIA) method for CyA using a commercially available FPIA kit, TDX[○!R] cyclosporine monoclonal whole blood, was modified. A fat emulsion for intravenous infusion, Intralips[○!R], was incorporated for dissolving the CyA extracted from the skin tissue, and a mixture of MeOH/purified water was used as the sample pretreatment medium instead of the precipitation reagent in the conventional FPIA kit intended for whole blood samples. These modifications enabled us to produce a reliable and the sensitive assay of CyA in skin tissue. The reproducibility (coefficient of variation), detection limit, and assay time for FE-FPIA were below 2%, 25 ng/ml, and about 24 min/24 samples, respectively, and were comparable with those for the whole blood samples determined by the conventional FPIA. Pre-purification of samples required by the HPLC assay is not needed in the FE-FPIA method. The usefulness of the FE-FPIA method in evaluating the topical pharmacokinetics of CyA in skin is discussed.

The absorption of an antibiotic, latamoxef sodium (LMOX), following the rectal administration of a suppository containing adjuvants was investigated. A lipophilic base (Witepsol H15) was used. The rectal absorption of LMOX following the administration of a suppository without adjuvants was very low. Diclofenac sodium (DF) was used as an absorption promoter; it enhances rectal membrane permeability. The blood level of LMOX following the addition of DF(10 mg) to the base was increased only about 1.3-fold compared with that achieved with LMOX alone (difference not significant); even with a higher dose of DF, the absorption of LMOX was not sufficient. The release rate of LMOX from the base was slow. When Tween 80, a non-ionic surfactant, was added to improve the release rate of LMOX, the rate was sufficiently increased. The rectal absorption of LMOX on the addition of both Tween 80 and DF was markedly increased compared to that achieved with LMOX alone or with DF. These results indicate that the rectal absorption of LMOX after administration by a suppository was sufficiently improved by enhancing both the release rate from the base and the membrane permeability of the rectum. Lymphatic uptake and blood levels of LMOX were also investigated after the rectal administration of the LMOX preparation containing both Tween 80 and DF; the lymphatic uptake of LMOX was significantly enhanced compared with the LMOX preparation in which only DF was used as an adjuvant. The mechanism whereby adjuvants lead to the absorption of a non-absorbable drug, and the subsequent drug transportation routes through the membrane are discussed.

The influence of suppository bases and adjuvants on the release rate of drugs and the absorption of non-absorbable drugs such as sulfanilic acid (SA) and sulfaguanidine (SG), was investigated following the rectal administration of suppositories. The suppository bases used were lipophilic bases such as Witepsol W 35, H 15, S 55, E 75 and hydrophilic base such as macrogol. SA was rapidly released from macrogol, W 35, H 15 and S 55, except E 75. On the other hand, SG was rapidly released from macrogol, whereas the release of SG from lipophilic bases was slow. Rectal absorption of SA and SG following administration of each drug alone in suppository form was slight. On the addition of diclofenac sodium (DF) as absorption promoter the blood levels of SA and SG released from all suppositories increased by about two to four fold compared with those suppositories containing only SA or SG, respectively. However, the absorption of SG still did not attain sufficient levels by the administration of DF only. The rectal absorption of SG was markedly increased by the release rate of the drug from the suppository. These results indicate that after administration of these suppositories the bioavailability of non-absorbable drugs was sufficiently improved by enhancing both the release rate from the suppositories and the rectal membrane permeability.

The effects of three kinds of cyclodextrins (CyDs), alpha-, beta- and gamma-CyD on biological membranes were investigated by changes in absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine and rectum using an in situ perfusion technique. The absorption of SA from the intestine was slight and was not affected by the addition of CyDs. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), the absorption of SA was increased compared with SA alone in the presence of only beta-CyD. Similar treatment with sodium deoxycholate (SDC) and sodium lauryl sulfate (SLS) to gastro-intestinal membrane showed the enhanced absorption of SA by the addition of beta-CyD. The mucin layer on the surface of the gastro-intestinal membrane may play an important role in the absorption of drugs. On the other hand, enhanced absorption of SA from the rat rectum was not induced by beta-CyD with or without pretreatment with N-Ac, SDC or SLS. Simultaneously, the release of neutral sugars in the perfusate after treatment with adjuvants was also observed with N-Ac, SDC and SLS. These results indicate that the mucin layer works as a barrier to the increased absorption of SA by beta-CyD.

The metabolism and pharmacokinetics of amino-penicillins such as ampicillin (AB-PC), hetacillin (IPAB-PC), talampicillin (TA-PC), amoxycillin (AM-PC) and cyclacillin (AC-PC) in man were investigated. An ion-pair reversed phase high performance liquid chromatographic method was developed for the simultaneous determination of parent penicillins and their metabolites in human urine. The time courses of urinary excretions of unchanged penicillins and metabolites (penicilloic acid (PA) and penamaldic acid (PM)) up to 8 hours after oral administration were determined by using the HPLC method. The moment analysis of urinary excretion rate-time curves gave mean residence times and excretion amounts of the various species. The ratios of excreted amounts to dose (500 mg) at infinite time were estimated to be as follows : (1) AB-PC : 29.4% for unchanged AB-PC, 4.3% for AB-PA and 2.0% for AB-PM (total 35.6%) ; (2) IPAB-PC : 51.8% for AB-PC, 8.7% for AB-PA and 3.9% for AB-PM (total 63.9%) ; (3) TA-PC : 68.8% for AB-PC, 10.2% for AB-PA and 4.5% for AB-PM (total 83.5%) ; (4) AM-PC : 58.9% for unchanged AM-PC, 15.6% for AM-PA and 6.9% for AM-PM (total 81.4%) ; and (5) AC-PC : 76.6% for unchanged AC-PC and 13.4% for AC-PA (total 90.0%). AC-PC gave no detectable amount of penamaldic acid. The rate constants for absorption, metabolism, and urinary excretion were estimated from the moments of the time course curves by using a one-compartment open model. The pharmacokinetic features of amino-penicillins and the prodrugs, are compared and discussed.

The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the permeability to marker drugs, sulfanilic acid and creatinine, was investigated in rat rectum using the in situ perfusion technique. Indomethacin (IM), phenylbutanone (PB), diclofenac sodium (DF), and aspirin (ASA) were used as NSAIDs. The permeability-enhancing effect increased in the following order : ASA

The transport mechanisms of cephalexin (CEX) and ampicillin (AB-PC) across rat jejunum were examined using the electrophysiological technique in vitro. From the experiments under the short-circuit condition, it became evident that the specific transport system participates in the mucosal-to-serosal transport of CEX, while AB-PC is transport only by the simple diffusion. In addition, the transport routes of these drugs were examined using the voltage-clamp technique. Salicylate, a model drug of the weak electrolyte, was transported mainly via a paracellular route, while CEX, in the absence of Na, penetrated the membrane via two routes, i.e. the transcellular route and the paracellular route. Similar result was obtained as to AB-PC. So it seems to be likely that these two drugs diffuse through the intestinal epithelium via the similar pathways in the Na-free condition.

Aqueous solutions of sodium deoxycholate, sodium lauryl sulfate, disodium ethylenediaminetetraacetate, and polyethylene glycol 400 were repeatedly perfused in the rectal lumen of rats. Changes in the permeability and the recovery of the altered histology of the rectal membrane were examined. An experimental apparatus which allowed perfusion of the adjuvant solutions in the rectal lumen without surgical operation was used. It was found that the epithelial cells affected by the adjuvants returned to the normal state within 2h after the pretreatment. However, the goblet cells did not show complete recovery even at 24h after the pretreatment, and the permeability of the membrane was still higher than the control value at that time. The permeability of the membrane on repeated treatment with the adjuvants was not increased as much as on the first treatment.

The effects of diclofenac sodium and disodium ethylenediaminetetraacetate (EDTA) on electrical parameters of rat jejunal membrane were investigated, together with measurement of the mucosal-to-serosal flux of sulphanilic acid or L-phenylalanine. Both adjuvants increased the flux rate of sulphanilic acid to a similar extent when added to the mucosal solution at 10 mM, but there were apparent differences in their effects on the electrical parameters. The addition of EDTA induced the gradual reduction in the membrane resistance (Rm) by 6–8 ohm cm−2, while the effect of diclofenac on Rm was complicated and concentration-dependent. The short circuit current (Isc) was reduced rapidly to the level of 30–40 μA cm−2 by the addition of diclofenac, but was less affected by EDTA. The flux rate of L-phenylalanine was decreased extensively by diclofenac or the 10 mM concentration of EDTA, suggesting an inhibition of carrier-mediated transport systems in the membrane. Together with our preceding communication (Yamashita et al 1985, J. Pharm. Pharmacol. 37: 512–513), it became obvious that the sites of action of diclofenac and EDTA were different, the former directly interacting with the epithelial cell to alter the permeability and functions of the cell membane, while the primary effect of EDTA could be at the intercellular junctions.

This investigation was concerned with the change of the bioavailability of a drug owing to the interaction of the drug-beta-cyclodextrin complex with bile salts in rat intestinal lumen. The absorption of sulfamethizole (SMZ) from rat intestinal lumen after administration of SMZ-beta-cyclodextrin complex was determined by a closed-loop method in the presence or absence of bile. The blood level of SMZ after administration of SMZ-beta-cyclodextrin complex was significantly decreased in comparison with that after administration of SMZ alone in bile duct-ligated rats. On the other hand, the blood level of SMZ after SMZ-beta-cyclodextrin administration in intact rats (bile duct non-ligated) or on the addition of sodium cholate was similar to the level in the case of SMZ alone. Thus, bile salts were found to act as a competing agent in the gastrointestinal tract.

The elimination of imipramine (IMP) from brain regions was investigated in rats after multiple intraperitoneal (i.p.) administration for 3 weeks. Brain regions could be divided into two classes as to IMP elimination in analogy with a single i.p. dose. IMP levels in the plasma, class A brain regions (cerebellum, mid-brain and medulla, striatum, posterior cortex and frontal cortex) and the initial phase of the curves for class B brain regions (hypothalamus, thalamus, hippocampus and nucleus accumbens) had identical elimination rate constants. They shifted in parallel depending on the dose as in the case of a single dose. On the other hand, the later phase of the curves in the class B brain regions shifted in parallel to the low concentration side with an elimination rate constant similar to that after a single dose. The high-affinity sites for IMP in class B brain regions seemed to be markedly decreased by multiple doses for 3 weeks.

The effect of experimental acute renal failure on the permeability and transport function of the intestinal membrane was analyzed in the isolated rat jejunum by using in vitro electrophysiogical methods. The mucosal-to-serosal flux rate sulfanilic acid (SA), which was used as a model of the polar drug, increased significantly in the membrane obtained from the rat with acute renal failure, indicating a reduction of the barrier function of the intestinal membrane. This effect of renal failure was neither dependent on the procedure used to induce the disease nor correlated with the extent of the disease state, shown by the level of blood urea nitrogen. Furthermore, it was clarified that the change in the permeability to SA occurred mainly in the transcellular pathway but not in the paracellular one. The electrical rezistance of the jejunal membrane did not change in rats with acute renal failure. Thus, it was suggested that the structure of the tight-junctional portion of the epithelial layer remained unchanged, while the permeability of the cellular membrane was altered by the disease state. The activity of the intestinal membrane to transport Na+ or glucose might not be influenced by the disease state since the transmembrane potential difference and the short-circuit current of the membrane showed no significant change from their normal values.

The effect of adjuvants such as sodium deoxycholate (SDC), sodium lauryl sulfate (SLS), disodium ethylenediaminetetraacetate (EDTA) and tetracycline hydrochloride (TC) on the permeability to water-soluble compounds with various molecular weights through the rat rectal membrane was evaluated by using an in situ technique. Creatinine, 14C-inulin, 125I-insulin, 125I-polyvinylpyrrolidone and 125I-albumin were selected as marker drugs. Significant increases in the permeability of the rectal membrane to the marker drugs were observed in the cases of SDC and SLS. On the other hand, the effect of EDTA, and especially TC, became smaller as the molecular weight of the marker drugs increased. The order of effectiveness of adjuvants on the permeability was SDC>SLS>EDTA>TC.

The effect of Tween-type surfactants on the permeability of the rectal membrane was investigated by determining the absorption and apparent rectal clearance of marker drugs, using the in situ perfusion technique in rats. The tested substances were polysorbates 85, 80, 60, 40, 21, and 20, and polyoxyethylene sorbitan 20. When these surfactants were added in aqueous solutions, they did not significantly affect the permeability. On the other hand, these surfactants affected the histological nature of the rectal tissue and enhanced the permeability when they were added in oil.