A new clustering model based on the seminal plasma/serum ratios of multiple trace element concentrations in male patients with subfertility.

Purpose: To investigate whether seminal plasma (SP)/serum ratios of multiple trace elements (TEs) can classify patients with male subfertility. Methods: SP/serum ratios of 20 TEs (lithium, sodium, magnesium, phosphorus, sulfur, potassium, calcium, manganese, iron, cobalt, copper, zinc, arsenic, selenium, rubidium, strontium, molybdenum, cesium, barium, and thallium) were calculated for healthy volunteers (n = 4) and those consulting for male subfertility (n = 245). Volunteer semen samples were collected by split ejaculation into early and subsequent fractions, and SP/serum ratio data were compared between fractions. The patients' SP/serum ratio data were used in an unsupervised clustering analysis and qualitatively compared with the data from the fractions of ejaculation from the volunteers. Semen quality parameters and pregnancy outcomes were compared between patient clusters. Results: The early fraction of volunteers was characterized by lower phosphorus and arsenic and 18 other higher TEs than the subsequent fraction. Cluster analysis classified patients into four distinct clusters, one sharing characteristics with the early fraction and another with the subsequent fraction. One cluster with the early fraction characteristics had significantly lower semen volume and higher pregnancy rates from spontaneous pregnancies or intrauterine insemination. Conclusions: Classification of patients based on SP/serum ratios of multiple TEs represents the dominance of fractions of ejaculation samples.

Next-generation sequencing in two cases of de novo acute basophilic leukaemia.

Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloid leukaemia (AML); therefore, few data are available about its biology. Herein, we analysed two ABL patients using flow cytometry and next-generation sequencing (NGS). Two cell populations were detected by flow cytometry in both patients. In Case no. 1, blasts (CD34+ , CD203c- , CD117+ , CD123dim+ ) and basophils (CD34- , CD203c+ , CD117± , CD123+ ) were identified, both of which were found by NGS to harbour the 17p deletion and have loss of heterozygosity of TP53. In Case no. 2, blasts (CD33+ , CD34+ , CD123- ) and basophils (CD33+ , CD34+ , CD123+ ) were identified. NGS detected NPM1 mutations in either blasts or basophils, and TET2 in both. These data suggest an overlap of the mutational landscape of ABL and AML, including TP53 and TET2 mutations. Moreover, additional mutations or epigenetic factors may contribute for the differentiation into basophilic blasts.

The Incidence of Para-Anastomotic Aneurysm After Open Repair Surgery for Abdominal Aortic Aneurysm Through Routine Annual Computed Tomography Imaging.

OBJECTIVE: Open repair surgery (ORS) for an abdominal aortic aneurysm (AAA) remains an important treatment option, but the incidence of para-anastomotic aneurysms is unclear. The purpose of this study was to estimate the incidence of para-anastomotic aneurysms and reveal secondary complications through routine annual computed tomography (CT) imaging. METHODS: One hundred and forty-seven patients who underwent ORS for AAA between January 2006 and December 2015 and received routine CT imaging surveillance were enrolled. RESULTS: The follow up period was 7.1 ± 2.7 years. The total follow up time of all patients was 1 041.1 years, and 958 CT images were collected (0.92 CT scans/year/patient). A proximal para-anastomotic aneurysm was detected in five patients (3.4%). Four of the five patients had aneurysmal dilation at the initial ORS (proximal diameter >25 mm), which enlarged during follow up; thus, a de novo proximal para-anastomotic aneurysm was observed in one patient (0.7%). The time between surgery and the diagnosis of all proximal para-anastomotic aneurysms was 5.7 ± 1.4 years, and the de novo proximal para-anastomotic aneurysm was detected at 11.8 years. The incidence of all para-anastomotic aneurysms at five and 10 years was 2.2% and 3.6%, and the incidence of the de novo para-anastomotic aneurysm was 0% at five and 10 years. Nine synchronous thoracic aortic aneurysms (TAAs) and seven metachronous TAAs were detected, and 16 patients (10.9%) had a TAA. Neoplasms were detected in 18 of 147 patients (12.2%), and the most dominant neoplasm was lung cancer. CONCLUSION: The incidence of para-anastomotic aneurysms was low; thus, abdominal and pelvic CT imaging every five years may be sufficient and consistent with the current AAA guidelines. In contrast, TAAs were diagnosed in a high percentage of patients, and based on these observations, routine CT imaging should be expanded to include the chest.

First case of an invasive Bacteroides dorei infection detected in a patient with a mycotic aortic aneurysm-raising a rebellion of major indigenous bacteria in humans: a case report and review.

BACKGROUND: Bacteroides dorei is an anaerobic gram-negative bacterium first described in 2006. Because of the high similarity in mass spectra between B. dorei and Bacteroides vulgatus, discriminating between these species is arduous in clinical practice. In recent decades, 16S rRNA gene sequencing has been a complementary method for distinguishing taxonomically close bacteria, including B. dorei and B. vulgatus, at the genus and species levels. Consequently, B. dorei has been shown to contribute to some diseases, including type 1 autoimmune diabetes mellitus and atherosclerotic diseases. However, there are no reports on invasive infectious diseases caused by B. dorei. This report describes the first case of direct invasion and colonisation of human tissue by B. dorei, thus providing a warning regarding the previously proposed application of B. dorei as a live biotherapeutic for atherosclerotic diseases. CASE PRESENTATION: A 78-year-old Japanese man complained of intermittent chest/back pain and was diagnosed with a mycotic thoracic aortic aneurysm by enhanced computed tomography on admission. Despite strict blood pressure control and empirical antibiotic therapy, the patient's condition worsened. To prevent aneurysmal rupture and eliminate infectious foci, the patient underwent surgical treatment. The resected specimen was subjected to tissue culture and 16S rRNA gene sequencing analysis to identify pathogenic bacteria. A few days after the surgery, culture and sequencing results revealed that the pathogen was B. dorei/B. vulgatus and B. dorei, respectively. The patient was successfully treated with appropriate antibacterial therapy and after improvement, was transferred to another hospital for rehabilitation on postoperative day 34. There was no recurrence of infection or aneurysm after the patient transfer. CONCLUSIONS: This report describes the first case of invasive infectious disease caused by B. dorei, casting a shadow over its utilisation as a probiotic for atherosclerotic diseases.

Detection of Macrophage Localization in the Abdominal Aortic Aneurysm Wall Using Ex Vivo Superparamagnetic Iron Oxide-Enhanced Magnetic Resonance Imaging.

BACKGROUND: Macrophages in the aneurysmal wall play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Superparamagnetic iron oxide (SPIO) is a macrophage-specific contrast agent that results in negative enhancement on magnetic resonance imaging (MRI). SPIO-enhanced MRI targeting the intraluminal thrombus of AAAs has been previously reported. However, macrophages in the media and adventitia of AAA wall have not been investigated in detail. This study aimed to evaluate macrophage localization using SPIO-enhanced MRI in the media and adventitia of AAA wall, as macrophages play a crucial role in AAA pathogenesis. METHODS: Here, we included study and control patients planning to undergo open surgery for AAA. The study patients received SPIO injection 2 days preoperatively (the SPIO group, n = 7), whereas the control patients did not receive this injection (the control group). Ex vivo MRI was performed on the harvested AAA wall in the SPIO group during the surgery. The concordance between the number of macrophages and berlin blue (BB)-stained areas was histologically evaluated in both groups. Moreover, the concordance between regions of interest in MR images and BB-stained areas was evaluated. RESULTS: The proportion of BB-stained macrophages was higher in the SPIO group (0.93; interquartile range [IQR], 0.83-0.95) than in the control group (0.03; IQR, 0.026-0.11) (P < 0.05), indicating uptake of SPIO by macrophages in the AAA wall. A significant positive correlation was found between the number of BB-stained macrophages and BB-stained areas using Kendall rank correlation coefficient in the SPIO group (τ = 0.58; P < 0.05). Significant correlations were found in the distributions of the region of interest of SPIO-enhanced MRI and BB-stained areas in the media and adventitia in 5 of 7 patients. CONCLUSIONS: Macrophages present in the media and adventitia of the AAA wall showed an uptake of the SPIO contrast agent injected 2 days prior, which were then detected by ex vivo MRI. This suggests that SPIO-enhanced MR images help detect the localization of macrophages on the AAA wall, indicating its potential to serve as a novel index for AAA pathogenesis.

Neutropenia and renal dysfunction due to intravesical cidofovir for virus-associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations.

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.

The Epidemiology of Micro-arteriovenous Fistulas in the Lower Legs.

BACKGROUND: Patients presenting with edema, skin redness, pain, and itching in their lower legs are common and encountered often in daily practice. However, although commonly recognized diseases such as deep venous thrombosis, stasis dermatitis due to varicose veins, lymphedema, and cellulitis are diagnosed correctly in most cases, micro-arteriovenous fistulas (AVFs) may often be overlooked due to low awareness and rarity. This study was carried out to evaluate the prevalence of micro-AVF in patients presenting with foot skin symptoms. METHODS: A total of 134 patients (184 limbs) visited the Department of Vascular Surgery at Kesennuma City Hospital with edema, skin redness, pain, and itching in their lower legs from January to September 2017 and were enrolled and followed up until November 2017. All patients received ultrasonic inspection of their symptomatic limb, and a blood test (white blood cell count, C-reactive protein, and d-dimer) was performed if needed. When micro-AVF was detected in one limb, the other limb was routinely inspected by ultrasonography. A computed tomography scan was performed with the patient's consent. Patients diagnosed with micro-AVF started compression therapy immediately and were followed up for at least 2 months. A surgical procedure was considered if the symptoms worsened. RESULTS: Micro-AVFs were detected in 24 limbs (13%, 24/184) of 14 patients (7 males and 7 females; age 70 ± 11.7 years). Four patients had unilateral skin symptoms with unilateral micro-AVFs and 7 patients had unilateral skin symptoms and bilateral micro-AVFs. Three patients had bilateral skin symptoms and bilateral micro-AVFs. Asymptomatic micro-AVFs were detected in 7 limbs. Subjective symptoms disappeared and skin appearance normalized in 14 limbs of 12 patients during the first 2 months with compression therapy only. Compression therapy was not effective in 3 limbs of 2 patients and they underwent vein ligation surgery. None of the patients had a surgical history or history of trauma in their lower legs. CONCLUSIONS: Among the lower legs presenting with skin symptoms, we detected micro-AVFs in 13% of limbs; therefore, micro-AVF of the lower leg is not as rare as previously thought. In addition, 10 of 14 patients (71%) had micro-AVFs of the lower leg bilaterally.

[Acquired hemophilia A with high-titer factor VIII inhibitor developing subsequent to clopidogrel administration].

An 80-year-old male was referred to our department for prolonged APTT (activated partial thromboplastin time) and subcutaneous hemorrhage. His medical history comprised alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and peripheral artery disease (PAD). For refractory HCC, he had received transcatheter arterial chemoembolization and was followed up regularly at our hospital. He underwent percutaneous transluminal angioplasty for PAD 10 months ago, and dual antiplatelet therapy with clopidogrel and cilostazol was initiated. Cilostazol was discontinued owing to subcutaneous hemorrhage 6 months ago. The prolonged APTT level, inhibitor pattern by cross-mixing test, and the presence of the inhibitor against factor VIII (449 Bethesda unit/ml) corroborated acquired hemophilia A (AHA). Thus, clopidogrel was discontinued for possible drug-induced AHA. After 4-week oral corticosteroid therapy, the APTT level recovered to normal. This case highlights two distinct features as follows: (1) possible relation to clopidogrel; and (2) despite extremely high titer of factor VIII inhibitor, his bleeding episodes were managed without antihemorrhagic agents. Here we present a case of clopidogrel-related AHA. Further accumulation of such cases is warranted to determine the potential correlation with clopidogrel and AHA.

Acute myocardial infarction due to simultaneous spasm of 3 coronary arteries that worsened over time.

Coronary artery spasm (CAS) rarely worsens from single-vessel to simultaneous multivessel CAS naturally, and simultaneous multivessel CAS leads to serious conditions such as cardiopulmonary arrest (CPA). A 77-year-old Japanese man who took medications for CAS was transferred to our hospital due to persistent chest pain. On arrival, his vital signs were stable, but his electrocardiogram (ECG) showed ST-segment elevation in leads II, III and aVF. Ventricular fibrillation developed suddenly. Although routine cardiopulmonary resuscitation (CPR) including intravenous administration of epinephrine was performed immediately, he could not be resuscitated. After initiation of percutaneous cardiopulmonary support (PCPS), there was a return of spontaneous circulation. His ECG showed exacerbation of myocardial ischemia with ST-segment elevation in leads I, II, III, aVL, aVF and V3-V6. Emergency coronary angiography revealed severe CAS of the right and left coronary arteries, which was relieved completely by intracoronary administration of nitrates. He was diagnosed with acute myocardial infarction due to simultaneous 3-vessel CAS that progressed over time. About 6h after arrival, he developed hemodynamic instability and died. CAS worsened from single-vessel to simultaneous 3-vessel spasm, and intracoronary administration of nitrates was effective in relieving CAS, which was documented by the ECG and coronary angiogram. Since CAS can progress over time, nitrates must be administered immediately. When CAS leads to CPA, epinephrine may be ineffective in CPR because of its vasoconstrictive effect on coronary arteries; therefore, PCPS should be initiated, and intracoronary nitrates should be administered.

[Autologous peripheral blood stem cell transplantation for treating primary central nervous system lymphoma: a single-center retrospective study].

Primary central nervous system lymphoma (PCNSL) is more difficult to treat than other lymphomas. Recently, it has been suggested that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is effective for treating PCNSL. In the present study, we retrospectively analyzed 12 patients with PCNSL at our hospital. Five young patients with good performance status (PS) received upfront ASCT. The conditioning regimen prior to ASCT with busulfan ＋ cyclophosphamide ＋ etoposide showed good prognosis (complete remission rate of 100%). In addition, the PS improved in patients treated with high-dose chemotherapy followed by ASCT, while it worsened in those treated without ASCT. Further investigations are needed to clarify inclusion/exclusion criteria and optimize conditioning regimens for ASCT.

[Aortic Root Pseudoaneurysm due to Avulsion of Aortic Valve Commissure Following to Infective Endocarditis;Report of a case].

A 40-year-old man presented to our hospital with fever and slight palpitation. The echocardiogram revealed bicuspid aortic valve, massive aortic regurgitation, and aneurysm of Valsalva sinus. Operative findings showed an aortic root pseudoaneurysm originating just below the avulsion of the right to left commissure. The orifice was closed with a part of a woven vascular graft, and the aortic valve was replaced with a mechanical valve. There was no sign of marked inflammation, although pathophysiologic findings indicated infective endocarditis. His postoperative course was uneventful.

The Risk Factors of Hamstring Strain Injury Induced by High-Speed Running.

Hamstring strain injury is a multifactorial and complex problem involving interactions among various factors. Information about risk factors for this injury is inconsistent among studies because the strong effects of confounding factors and injury situations are often ignored. We investigated the relationship between hamstring strain induced by high-speed running and intrinsic risk factors, including hip muscle morphology and function, by excluding the influences of confounding factors. Sixty-one male track and field athletes (age, 19.6 ± 1.1 years; 95% confidence interval, 19.3-19.9) who often performed high-speed running were monitored throughout one season. Before the season, we measured hip and knee strength, muscle thickness of the gluteus maximus and biceps femoris, and hip and knee joint range of motion (ROM). We also obtained information about each athlete's history of hamstring injury by questionnaire. Eighteen athletes sustained hamstring strain injuries induced by high-speed running. Eighteen uninjured athletes who had the same profile of confounding factors as the injured athletes were selected as controls. Previously injured athletes had a significantly higher injury rate than uninjured athletes (p < .05; odds ratio, 2.85). No other measurements had a significant relationship with the occurrence of injury. However, passive hip ROM (flexion and extension) tended to be larger in the injured than control group. A history of hamstring strain was a strong risk factor for hamstring strain injury, and it may affect other factors. Therefore, the risk factors for hamstring strain injury should be investigated by eliminating the impact of a history of hamstring strain.

Oral Steroid Use and Abdominal Aortic Aneurysm Expansion　- Positive Association.

BACKGROUND: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041). CONCLUSIONS: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.

Relationship between isometric contraction intensity and muscle hardness assessed by ultrasound strain elastography.

INTRODUCTION: Ultrasound elastography is used to assess muscle hardness or stiffness; however, no previous studies have validated muscle hardness measures using ultrasound strain elastography (SE). This study investigated the relationship between plantar flexor isometric contraction intensity and gastrocnemius hardness assessed by SE. We hypothesised that the muscle would become harder linearly with an increase in the contraction intensity of the plantar flexors. METHODS: Fifteen young women (20.1 ± 0.8 years) performed isometric contractions of the ankle plantar flexors at four different intensities (25, 50, 75, 100% of maximal voluntary contraction force: MVC) at 0° plantar flexion. Using SE images, the strain ratio (SR) between the muscle and an acoustic coupler (elastic modulus 22.6 kPa) placed over the skin was calculated (muscle/coupler); pennation angle and muscle thickness were measured for the resting and contracting conditions. RESULTS: SR decreased with increasing contraction intensity from rest (1.28 ± 0.20) to 25% (0.99 ± 0.21), 50% (0.61 ± 0.15), 75% (0.34 ± 0.1) and 100% MVC (0.20 ± 0.05). SR decreased linearly (P < 0.05) with increasing MVC from rest to 75% MVC, but levelled off from 75 and 100% MVC. SR was negatively correlated with pennation angle (r = -0.80, P < 0.01) and muscle thickness ( r= -0.78, P< 0.01). CONCLUSION: SR appears to represent muscle hardness changes in response to contraction intensity changes, in the assumption that the gastrocnemius muscle contraction intensity is proportional to the plantar flexion intensity. We concluded that gastrocnemius muscle hardness changes could be validly assessed by SR, and the force-hardness relationship was not linear.

Graft placement with an omental flap for ruptured infective common iliac aneurysm in a patient with a continuous flow left ventricular assist device: alternative surgical approach avoiding driveline injury and pathogen identification by 16S ribosomal DNA gene analysis.

Patients supported by mechanical circulatory support have to wait for longer periods for heart transplantation in Japan. Infective events are a major complication and influence survival. Here, we present the case of a patient with an implantable left ventricular assist device for 6 months who had the complication of ruptured infective common iliac aneurysm. Graft placement with an omental flap was successfully performed via the alternative surgical approach to avoid percutaneous driveline injury. In samples of aortic specimens, 16S ribosomal DNA gene analysis identified Helicobacter cinaedi. Complete removal of the infected tissue and correct pathogen identification may have been relevant to the good clinical course.

Sustained myocardial production of stromal cell-derived factor-1α was associated with left ventricular adverse remodeling in patients with myocardial infarction.

The role of stromal cell-derived factor-1α (SDF-1α) expressed in infarcted myocardium is unknown in humans. We examined whether SDF-1α produced in an infarcted myocardial lesion may play a role in left ventricle (LV) remodeling and dysfunction in patients with acute myocardial infarction (AMI). We measured SDF-1α levels in plasma obtained from aortic root (AO) and anterior interventricular vein (AIV) in the early phase (2 wk after MI) and the chronic phase (6 mo after MI) in 80 patients with anterior MI. An increment in SDF-1α level from AO to AIV, reflecting SDF-1α release from infarcted myocardium, was more frequent in patients with MI in the early phase of MI [n = 52 (65%), P = 0.03] but not in the chronic phase of MI [n = 46 (58%), P = 0.11] compared with that in control patients [n = 6/17 (35%)]. On linear regression analysis, the transmyocardial gradient in SDF-1α level in the chronic phase of MI was correlated with percentage changes in LV end-diastolic volume index (r = 0.39, P < 0.001), LV end-systolic volume index (r = 0.38, P < 0.001), and LV ejection fraction (r = -0.26, P = 0.01) 6 mo after AMI. By contrast, the transmyocardial gradient of SDF-1α in the early phase of MI had no significant correlations. In conclusion, the production of SDF-1α in infarcted myocardium in the chronic phase of MI was associated with LV adverse remodeling and progressive dysfunction in AMI survivors.

Gene ablation of carnitine/organic cation transporter 1 reduces gastrointestinal absorption of 5-aminosalicylate in mice.

5-Aminosalicylic acid (5-ASA) is an orally administered therapeutic agent for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. We hypothesized that the absorption of 5-ASA is mediated by the polyspecific carnitine/organic cation transporter (OCTN1/SLC22A4), based on the similarity of chemical structure between 5-ASA and other OCTN1 substrates. Therefore, we examined the involvement of this transporter in the disposition of 5-ASA in vivo by using octn1 gene knockout (octn1(-/-)) mice. After oral administration of 5-ASA, the plasma concentrations of 5-ASA and its primary metabolite, N-acetyl-5-aminosalicylate (Ac-5-ASA), in octn1(-/-) mice were much lower than those in wild-type mice. The time required to reach maximum plasma concentration was also delayed in octn1(-/-) mice. On the other hand, the plasma concentration profiles of both 5-ASA and Ac-5-ASA after intravenous administration of 5-ASA (bolus or infusion) were similar in the two strains. Uptake of 5-ASA from the apical to the basal side of isolated small-intestinal tissues of octn1(-/-) mice, determined in an Ussing-type chamber, was lower than that in wild-type mice. Further, uptake of 5-ASA in HEK293 cells stably transfected with the OCTN1 gene, assessed as the sum of cell-associated 5-ASA and Ac-5-ASA, was higher than that in HEK293 cells transfected with the vector alone. Overall, these results indicate that OCTN1 is involved, at least in part, in the gastrointestinal absorption of 5-ASA.

Acute Changes in Peripheral Vascular Tonus and Systemic Circulation during Static Stretching.

This study aimed to investigate the acute effect of static stretching (SS) on peripheral vascular tonus and to clarify the effect of SS on systemic circulation. Twenty healthy young male volunteers performed a 1-min SS motion of the right triceps surae muscle, repeated five times. The peripheral vascular tonus (|d/a| ratio) was obtained using second derivatives of the photoplethysmogram readings before, during, and after SS. Heart rate and blood pressure (BP) were also measured. The |d/a| ratio and BP were transiently, but significantly, elevated during SS and returned to baseline immediately after SS. Furthermore, we observed a significant correlation between the amount of change in the |d/a| ratio and the ankle range of motion during SS (r = 0.793 to 0.832, P = 0.01). These responses may be caused by mechanical stress during SS.

Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans.

Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC(50) of 0.05 µM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC(50) of 0.1 µM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans.