Peptides Derived from Soybean ß-Conglycinin Induce the Migration of Human Peripheral Polymorphonuclear Leukocytes.

Food-derived peptides have various biological activities. When food proteins are ingested orally, they are digested into peptides by endogenous digestive enzymes and absorbed by the immune cell-rich intestinal tract. However, little is known about the effects of food-derived peptides on the motility of human immune cells. In this study, we aimed to understand the effects of peptides derived from a soybean protein ß-conglycinin on the motility of human peripheral polymorphonuclear leukocytes. We illustrated that MITL and MITLAIPVNKPGR, produced by digestion using in-vivo enzymes (trypsin and pancreatic elastase) of ß-conglycinin, induces the migration of dibutyryl cAMP (Bt2 cAMP)-differentiated human promyelocytic leukemia 60 (HL-60) cells and human polymorphonuclear leukocytes in a dose- and time-dependent manner. This migration was more pronounced in Bt2 cAMP-differentiated HL-60 cells; mRNA expression of formyl peptide receptor (FPR) 1 increased significantly than in all-trans-retinoic acid (ATRA)-differentiated HL-60 cells. This migration was inhibited by tert-butoxycarbonyl (Boc)-MLP, an inhibitor of FPR, and by pretreatment with pertussis toxin (PTX). However, the effect was weak when treated with WRW4, a selective inhibitor of the FPR2. We then demonstrated that MITLAIPVNKPGR induced intracellular calcium responses in human polymorphonuclear leukocytes and Bt2 cAMP-HL60 cells. Furthermore, pre-treatment by fMLP desensitized the calcium response of MITLAIPVNKPGR in these cells. From the above, MITLAIPVNKPGR and MITL derived from soybean ß-conglycinin induced polymorphonuclear leukocyte migration via the FPR1-dependent mechanism. We found chemotactic peptides to human polymorphonuclear leukocytes, which are the endogenous enzyme digests of soybean protein.

Prediction model for milk transfer of drugs by primarily evaluating the area under the curve using QSAR/QSPR.

PURPOSE: Information on milk transferability of drugs is important for patients who wish to breastfeed. The purpose of this study is to develop a prediction model for milk-to-plasma drug concentration ratio based on area under the curve (M/PAUC). The quantitative structure-activity/property relationship (QSAR/QSPR) approach was used to predict compounds involved in active transport during milk transfer. METHODS: We collected M/P ratio data from literature, which were curated and divided into M/PAUC ≥ 1 and M/PAUC < 1. Using the ADMET Predictor® and ADMET Modeler™, we constructed two types of binary classification models: an artificial neural network (ANN) and a support vector machine (SVM). RESULTS: M/P ratios of 403 compounds were collected, M/PAUC data were obtained for 173 compounds, while 230 compounds only had M/Pnon-AUC values reported. The models were constructed using 129 of the 173 compounds, excluding colostrum data. The sensitivity of the ANN model was 0.969 for the training set and 0.833 for the test set, while the sensitivity of the SVM model was 0.971 for the training set and 0.667 for the test set. The contribution of the charge-based descriptor was high in both models. CONCLUSIONS: We built a M/PAUC prediction model using QSAR/QSPR. These predictive models can play an auxiliary role in evaluating the milk transferability of drugs.

Evaluation of a Webinar for Pharmacists Learning Basic Clinical-Oncology during COVID-19 Pandemic in Japan.

It is essential for oncology pharmacists to update their knowledge, skills, and ethical attitudes. The Japanese Society of Pharmaceutical Oncology is an academic society for healthcare professionals involved in cancer treatment. It has conducted in-person seminars every year to cultivate the knowledge necessary for practicing advanced cancer medicine. Owing to the coronavirus disease (COVID-19) pandemic, the society was obligated to conduct a web-based seminar this year. A questionnaire survey was conducted before and after the webinar to explain how it works and to assess the learning attitudes of beginner and moderately skilled pharmacists in the field of oncology. Questionnaire surveys were conducted with the participants before and after watching the webinar. The questionnaires sought to determine participants' perspectives on the webinar and their knowledge of the seven modules. Of the 1756 webinar attendees, 1661 (94.6%) answered the pre-webinar survey and 1586 (90.3%) answered the post-webinar survey. Results indicate that the median post-webinar knowledge score was significantly higher than the median pre-webinar score (p < 0.001) in all modules. Principal component analysis of the degree of knowledge of seven modules revealed that the improved score group consisted of those from younger age groups, with less experience as pharmacists, non-society members, and those with less experience in past society seminars. Moreover, the web-based seminar provided a uniform learning effect throughout the country without distinguishing between urban and rural learners. The web-based educational program was an acceptable educational tool for Japanese oncology pharmacists.

Evaluation of factors related to overdose in patients with impaired consciousness who are transported by emergency medical services: an age-specific research.

BACKGROUND: Drug overdose accounts for most of the admissions to the emergency department. Prescription drugs, most of which are psychotropic medications, are often misused for drug overdose. The purpose of this study was to investigate the association between overdose in patients transported with disorders of consciousness and psychotropic medications administered prior to transport, so as to enable quick differentiation of drug overdose patients from patients with disorders of consciousness. METHODS: We evaluated 222 patients transported to the Advanced Critical Care Center of Teikyo University Hospital due to disorders of consciousness. The patients were categorized into two groups: overdose group (n = 128) and control group with other disorders of consciousness (n = 94). Logistic regression models were used to assess the association between disorders of consciousness due to drug overdose and psychotropic drugs prescribed before emergency transportation based on sex and age. RESULTS: According to multivariate logistic regression analysis, only female sex (odds ratio [OR] 4.54, 95% confidence interval [CI] 2.43-8.05, P < 0.0001) was associated with overall overdose. Results from the univariate logistic regression analysis showed that in the group of patients aged 40-50 years, female sex (OR 4.36, 95% CI; 1.54-12.4, P = 0.006) and the use of psychotropic drugs (OR 5.05, 95% CI; 1.75-14.6, P = 0.003), benzodiazepines (OR 4.64, 95% CI; 1.61-13.4, P < 0.05), antidepressants (OR 11.4, 95% CI; 2.35-55.8, P = 0.003), and anticonvulsants (OR 4.46, 95% CI; 1.11-17.9, P = 0.035) were associated with overdose. According to multivariate logistic regression analysis, female sex (OR 4.44, 95% CI; 1.37-14.3, P = 0.013) and antidepressants (OR 7.95, 95% CI; 1.21-52.1, P = 0.031) were associated with overdose patients aged 40-50 years. CONCLUSIONS: As a reference in distinguishing overdose in women in their 40s and 50s who present with impaired consciousness, attention may need to be paid to the type of psychotropic drug used, especially antidepressants.

Evaluation of a web-based educational programme for pharmacists during the COVID-19 pandemic in Japan.

WHAT IS KNOWN AND OBJECTIVE: Continuing education is essential for pharmacists to acquire and maintain the knowledge, skills, and ethical attitudes necessary for clinical practice. However, with the emergence of COVID-19, the social circumstances and face-to-face learning environments have changed. The objectives of this study were to determine Japanese pharmacists' perception of a web-based educational programme in oncology, and assess changes in their understanding of pharmaceutical care in oncology before and after their participation in the webinar. METHODS: Questionnaire-based surveys were conducted for the participants of the web-based educational programme to determine their perspectives on the webinar, and their degree of comprehension of the five cancer types covered before and after watching the webinar. RESULTS AND DISCUSSION: Of the 1936 pharmacists taking the programme, all participated in the pre-webinar survey, and 1861 (96.1%) in the post-webinar survey. Compared with previous seminars that were held in the offline mode before the COVID-19 pandemic, 76.8% of respondents were significantly satisfied with the web-based educational programme. The median post-webinar comprehension scores in all modules were significantly higher than the median pre-webinar scores (p < 0.0001). A majority of the participants agreed that a web-based educational programme was satisfactory in acquiring knowledge. WHAT IS NEW AND CONCLUSION: This web-based educational programme was effective for Japanese pharmacists for postgraduate education in pharmaceutical care in oncology. To the best of our knowledge, our study is the first to report the effectiveness of a web-based educational programme for oncology pharmacists using a large population.

Effect of antipsychotics on breast tumors by analysis of the Japanese Adverse Drug Event Report database and cell-based experiments.

BACKGROUND: Since antipsychotics induce hyperprolactinemia via the dopamine D2 receptor, long-term administration may be a risk factor for developing breast tumors, including breast cancer. On the other hand, some antipsychotic drugs have been reported to suppress the growth of breast cancer cells in vitro. Thus, it is not clear whether the use of antipsychotics actually increases the risk of developing or exacerbating breast tumors. The purpose of this study was to clarify the effects of antipsychotic drugs on the onset and progression of breast tumors by analyzing an adverse event spontaneous reporting database and evaluating the proliferation ability of breast cancer cells. METHODS: Japanese Adverse Drug Event Report database (JADER) reports from April 2004 to April 2019 were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. Reports of females only were analyzed. Adverse events included in the analysis were hyperprolactinemia and 60 breast tumor-related preferred terms. The reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) were used to detect signals. Furthermore, MCF-7 cells were treated with haloperidol, risperidone, paliperidone, sulpiride, olanzapine and blonanserin, and cell proliferation was evaluated by WST-8 assay. RESULTS: In the JADER analysis, the IC signals of hyperprolactinemia were detected with sulpiride (IC, 3.73; 95% CI: 1.81-5.65), risperidone (IC, 3.69; 95% CI: 1.71-5.61), and paliperidone (IC, 4.54; 95% CI: 2.96-6.12). However, the IC signal of breast tumors was not observed with any antipsychotics. In cell-based experiments, MCF-7 cells were treated with six antipsychotics at concentrations of 2 and 32 µM, and none of the drugs showed any growth-promoting effects on MCF-7 cells. On the other hand, blonanserin markedly suppressed the growth of MCF-7 cells at a concentration of 32 µM, and the effect was concentration dependent. CONCLUSIONS: Analysis of the JADER using the IC did not show breast tumor signals due to antipsychotic drugs. In in vitro experiments, antipsychotics did not promote MCF-7 cell proliferation whereas blonanserin suppressed MCF-7 cell growth. Further research on the effects of blonanserin on the onset and progression of breast tumor is expected.

Structural Requirements for Uptake of Diphenhydramine Analogs into hCMEC/D3 Cells Via the Proton-Coupled Organic Cation Antiporter.

There is increasing evidence that a proton-coupled organic cation (H+/OC) antiporter facilitates uptake of various central nervous system-active drugs, such as the histamine H1 receptor antagonist diphenhydramine, into the brain. The purpose of this study was to clarify the structural requirements for H+/OC antiporter-mediated uptake into hCMEC/D3 cells, an established in vitro model of the human blood-brain barrier, by using a series of diphenhydramine analogs. For this purpose, we synthesized seven tertiary amine analogs and three amide analogs. Uptake of all the amines was facilitated by an outwardly directed H+ gradient and inhibited by pyrilamine, a typical substrate and a strong inhibitor of the H+/OC antiporter. Further, uptake of most of the amines was trans-stimulated by pyrilamine. Uptake of the amines was 21 times faster than that of the amides on average, even though the lipophilicity (log D7.4) of the amines is lower than that of the amides. Amines containing a pyrrolidine or piperidine ring showed the highest uptake rates. Our results suggest that an amine moiety, especially a heterocyclic amine moiety, is important for recognition and transport by the H+/OC antiporter.

Relationship between the effects of food on the pharmacokinetics of oral antineoplastic drugs and their physicochemical properties.

BACKGROUND: Food is known to affect drug absorption by delaying gastric emptying time, altering gastrointestinal pH, stimulating bile flow, increasing splanchnic blood flow, or physically interacting with drugs. Although food is known to affect the pharmacokinetics of oral antineoplastic drugs, the relationship between the effects of food and the physicochemical properties of drugs remains unclear. METHODS: In this study, we surveyed the literature on three kinds of pharmacokinetic changes, AUC ratio, Cmax ratio and Tmax ratio, in the fasted and fed state for 72 oral antineoplastic drugs that were listed on the drug price standard in May 2018 in Japan. We further predicted the physicochemical properties from the 2D chemical structure of the antineoplastic drugs using in silico predictions. RESULTS: As a result of analyzing the relationship between the effects of food and physicochemical properties, we found that compounds that show increased absorption in the fed state had higher logP and lower solubility in fasted-state simulated intestinal fluid (FaSSIF). However, compounds with delayed absorption had higher solubility in FaSSIF. Furthermore, as a result of decision tree analysis, it was classified as AUC increase with logP ≥4.34. We found that an AUC increase in the fed state did not occur with compounds with low lipid solubilities (logP < 1.59). From these results, it is predicted that 7 compounds out of the 24 compounds for which the effects of food are unknown are at risk for increased absorption in the fed state and that no increase in absorption would occur in 13 compounds. CONCLUSION: In this study, we found that drugs that will show increased absorption in the fed state and drugs for which absorption is not dependent on food can generally be predicted by logP. These results suggest that logP can be a useful parameter for predicting the effects of food on drug absorption.

Utility and effectiveness of Symbicort® Turbuhaler® (oral inhalation containing budesonide and formoterol) in a patient with severe asthma after permanent tracheostomy.

BACKGROUND: The utility and effectiveness of inhalational asthma therapy in patients with a permanent tracheostomy has not been established. Previously, a few studies reported the use of nebulizer-type inhalers for treating these patients. Symbicort® Turbuhaler® (Symbicort) is an orally inhaled dry powder containing the corticosteroid budesonide and the bronchodilator formoterol. There are no reports describing the successful use of Symbicort in patients with a permanent tracheostomy. CASE PRESENTATION: We describe the case of a woman with poorly controlled severe asthma after a permanent tracheostomy. She had developed thyroid cancer with tracheal invasion for which right thyroid lobectomy and tracheal and esophageal resection were performed, with subsequent construction of a permanent tracheostomy. In our case, prior to surgery, asthma control had been improved by adding a bronchodilator-the long-acting muscarinic antagonist tiotropium-and the anti-IgE antibody agent omalizumab to single maintenance and reliever therapy (SMART) using Symbicort; surgery was then performed. After surgery, asthma control worsened as a result of a change from Symbicort to budesonide nebulizer and a tulobuterol patch. In order to resume SMART therapy, an In-Check® inspiratory flow meter was used to measure and assess whether the inspiratory flow rate was sufficient for a dry-powder inhaler. Inhalation guidance was provided. On inhalation with the tracheostomy closed at the same time, the inspiratory flow rate was 43 L/min at the maximum. This was judged to be sufficient for the effect of Symbicort, and thus the inhaler was changed to Symbicort. Asthma symptoms promptly improved, and the patient was subsequently discharged. CONCLUSIONS: The use of Symbicort resulted in improved asthma control in a patient with severe asthma following a permanent tracheostomy. Thus, it is suggested that inhalation powder could be an option for patients with permanent tracheostomy.

New low-dose liquid pilocarpine formulation for treating dry mouth in Sjögren's syndrome: clinical efficacy, symptom relief, and improvement in quality of life.

BACKGROUND: Patients with Sjögren's syndrome (SS) typically present clinically with xerostomia (dry mouth) because of progressive damage to the exocrine glands. We developed a new, low-dose pilocarpine/sodium alginate (LPA) solution with pilocarpine hydrochloride to inhibit systemic adverse effects by administering via the oral mucosa. The purpose of this study was to assess its stability, safety, and efficacy. METHODS: The pilocarpine concentration in an LPA liquid formulation was measured 3, 7, 14, and 28 days after preparation to assess its stability. A prospective clinical trial was undertaken to assess the efficacy and safety of the LPA solution as a symptomatic treatment for dry mouth in SS. Patients (n = 24) with clinically significant xerostomia were enrolled after providing written informed consent. Whole-mouth salivary flow rate was measured twice; immediately before and 60 min after LPA application. Symptoms were assessed by questionnaire with visual analog scales or checkboxes before the first application (baseline), and then once daily for 7 days. RESULTS: The pilocarpine content 3, 7, 14, and 28 days after preparation showed no marked change, confirming its stability. Salivary flow was significantly increased from 0.076 ± 0.092 g/30 s to 0.122 ± 0.140 g/30 s 60 min after LPA administration (P < 0.001). Dry mouth and thirstiness showed significant improvement compared with that of baseline (P ≤ 0.01). The only adverse effect was sweating, and no serious drug-related adverse events were reported. CONCLUSIONS: This new, low-dose pilocarpine formulation was well-tolerated and resulted in significant improvements in symptoms of dry mouth and other xerostomic conditions in patients with SS. TRIAL REGISTRATION: The study approval number in the institution; 08-068-2. Registered January 19, 2009. UMIN000029307. Registered 27 September 2017 (retrospectively registered).

The influence of dietary peptide inhibitors of angiotensin-converting enzyme on the hypotensive effects of enalapril.

BACKGROUND: Enalapril is an antihypertensive medicine that inhibits angiotensin I-converting enzyme (ACE). The present study investigated interactions between enalapril and a fermented milk product (FMP) containing the ACE-inhibitory peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP). METHODS: Single-dose and long-term (6-week) in vivo studies were used to investigate the effects of enalapril and FMP on blood pressure in spontaneously hypertensive rats. RESULTS: Single-dose oral administration of concomitant enalapril and FMP (VPP, IPP: 3.5 mg/kg) produced a lower antihypertensive effect than enalapril monotherapy. However, this effect was not observed in animals administered a lower dose of FMP (VPP, IPP: 1.75 mg/kg) along with enalapril. In rats administered enalapril concomitantly with a fish protein product (FPP) containing a different ACE inhibitory peptide (Leu-Lys-Pro-Asn-Met), significant attenuation of the antihypertensive effect was also observed 1 and 2 h after administration, as compared to enalapril monotherapy. During a 6-week oral administration study, the enalapril monotherapy group showed significant antihypertensive effects compared to those observed in the controls on day 28. Oral administration of enalapril and FMP, with a 1-h interval between doses, resulted in significant antihypertensive effects on day 35, indicating a delayed onset in comparison to enalapril monotherapy. In rats receiving enalapril monotherapy for 28 days, followed by 14 days of concomitant FMP, significant antihypertensive effects were observed after day 35, and these did not differ significantly from the effects observed during enalapril monotherapy. CONCLUSIONS: The present findings suggested that long-term concomitant intake of FMP and enalapril could influence the antihypertensive effects of this drug.

[Efficacy of local steroid injection on rat skin lesions induced by extravasation of vesicant anticancer drugs].

The efficacy of local steroid injection on the extravasation of vesicant anticancer drugs is controversial. In this study, the efficacy of local steroid injection was evaluated macroscopically and histologically in the extravasation models of doxorubicin (DXR), vinorelbine (VNR), and paclitaxel (PTX)in rats. Macroscopically, gross skin lesions were reduced by local steroid injections in rats treated with DXR and VNR. PTX did not cause gross skin lesions in most rats regardless of local steroid injection. Histologically, however, DXR, VNR, and PTX all induced deep tissue lesions such as edema, inflammation, and necrosis. Therefore, the effect of local steroid injection seemed to be minimal. In particular, DXR induced extensive necrosis in the subcutaneous and muscle tissues. VNR-induced skin lesions were milder than those induced by DXR, but had full thickness. Lesions caused by PTX were the mildest. These findings suggest that although local steroid injections could serve a primary role in diluting anticancer drugs and reducing gross skin lesions by their anti-inflammatory effect, they have less ability for suppressing deep-tissue lesions developing over time.

Enhancement or Suppression of ACE Inhibitory Activity by a Mixture of Tea and Foods for Specified Health Uses (FOSHU) That Are Marketed as "Support for Normal Blood Pressure".

The ACE inhibitory activities of mixtures of FOSHUs (Healthya, Goma-Mugicha, Lapis Support and Ameal) were examined in order to identify any antihypertensive interactions. Among combinations of Healthya with other samples that contain active peptides, only that with Ameal was found to have no inhibitory activity. Enhanced activity was observed in 2 other mixtures. The activity of a mixture of tea polyphenols and the whey component extracted from an Ameal solution was significantly decreased, thus demonstrating that whey protein lowered the ACE inhibitory activity of Healthya. Although oral administration of tea polyphenols alone significantly decreased SBP in SHR at 2 and 4 hr, combined administration with Ameal failed to decrease SBP at the same time points. In conclusion, the simultaneous intake of tea and FOSHUs that contain active peptides might affect daily self-antihypertensive management via enhancement or suppression of ACE inhibitory activity.

MDR1 gene polymorphism in Japanese patients with schizophrenia and mood disorders including depression.

P-Glycoprotein (ABCB1-type P-gp), a membrane protein encoded by the multi drug resistant gene (MDR1), expressing on the blood brain barrier protects the brain from many drugs including dexamethasone. Psychiatric disorders, schizophrenia and depression, have known to have abnormal hypothalamus-pituitary-adrenal (HPA) activity, which is assessed by non-suppression of cortisol in dexamethasone suppression test. The poor response to dexamethasone in these patients' population suggested the impaired activity on dexamethasone penetration into the brain via P-gp, which was associated with MDR1 polymorphisms. We, therefore, examined five SNPs of the MDR1 gene, -1517 T>C (promoter), -41 A>G (intron -1), -129 T>C (exon 1b), 2677 G>A,T (exon 21) and 3435 C>T (exon 26), in Japanese patients with schizophrenia (n=121) and mood disorders (n=62), and compared with the control subjects (n=160). The frequency of MDR1 mutant alleles at -1517, -41 and -129 in patients with mood disorders was significantly lower (2.4, 5.6, 2.4%, respectively) than those of controls (7.8, 13.7, 7.8%, respectively) (p<0.05). The frequencies of MDR1 2677 G/A and A/A genotype in mood disorders was significantly higher (17.7, 6.5%, respectively) than controls (11.2, 0%, respectively) (p<0.05). The 2677A allele frequency in mood disorders (20.2%) was significant higher than controls (10.9%) (p<0.05). Haplotype of 129-2677-3435 (T-A-C) in mood disorders was significantly higher (14.4%) than controls (8.0%) (p<0.05). There was no significant difference in allele and genotype frequencies between the patients with schizophrenia and controls. These findings suggested that predispose to mood disorders, not schizophrenia, was associated with possible alteration of P-gp activities corresponding MDR1 polymorphism at least partly.

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.

OBJECTIVES: Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. METHODS: Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. RESULTS: CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). CONCLUSION: We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.

Effect of rabeprazole on MDR1-mediated transport of Rhodamine 123 in Caco-2 and Hvr100-6 cells.

The aim of our study was to investigate the effects of rabeprazole, a proton pump inhibitor, on MDR1 expressed on human colon carcinoma cell line, Caco-2, and MDR1-overexpressing human cervical carcinoma cell line, HeLa cells selected by exposure to 100 nM vinblastine (Hvr100-6 cells). Inhibitory effects of rabeprazole on MDR1-mediated transport of Rhodamine123 were examined in these cells. A thousand micro molar rabeprazole increased Rhodamine 123 uptakes in Caco-2 and Hvr100-6 cells by 68% and 185%, respectively. No significant effects of rabeprazole were observed at the concentration of 1-100 microM. Since rabeprazole did not show any effects on Rhodamine 123 transport via MDR1 at the plasma levels (approximately 1 microM), it was considered that the drug interaction with MDR1 substrates would be minimal even though the interaction occurred in the patients with rabeprazole treatment.

Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations.

The aim of this study was to investigate the effects of the proton pump inhibitors (PPIs), lansoprazole and rabeprazole, on tacrolimus pharmacokinetics in healthy volunteers with mutations in the cytochrome P450 (CYP) 2C19 gene (CYP2C19). An open-label crossover study was performed with 19 healthy subjects. Tacrolimus (2 mg) was administered orally with and without lansoprazole (30 mg per day for 4 days) or rabeprazole (10 mg per day for 4 days). Blood concentrations of tacrolimus were determined before and 1, 2, 4 and 8 h after dosing. Genotyping for CYP2C19 was conducted by a polymerase chain reaction-restriction fragment length polymorphism method. Coadministration of lansoprazole significantly decreased the oral tacrolimus clearance, resulting in an increase in the area under the blood concentration-time curve (AUC0-8) (control vs with lansoprazole: 29.7 +/- 3.5 vs 44.1 +/- 5.0 ng h mL(-1), P < 0.05). Large individual variation was observed in the effects of lansoprazole on tacrolimus AUC0-8 owing to CYP2C19 genotype status. The percent change for tacrolimus AUC0-8 in subjects with and without CYP2C19 mutant alleles was 81% and 29%, respectively. Coadministration of rabeprazole also increased the mean AUC0-8 of tacrolimus, but the difference was not statistically significant. These observations suggest that drug interaction between tacrolimus and lansoprazole occurs in subjects with higher lansoprazole blood concentrations corresponding to CYP2C19 genetic status. In contrast, rabeprazole has minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status.