Pulmonary vascular resistance and compliance in individuals with trisomy 18.

Individuals with trisomy 18 (T18) usually have congenital heart disease, often with pulmonary hypertension, which is associated with poor outcomes. This study aimed to explore the characteristics of pulmonary circulation including pulmonary vascular resistance (Rp) and compliance (Cp) among them. We retrospectively reviewed cardiac catheterization data in subjects with T18, trisomy 21 (T21), and without chromosomal anomaly (control group) who were referred due to heart failure associated with ventricular septal defect between 2000 and 2020. Pulmonary hemodynamic parameters including Rp and Cp were compared between these groups. We studied 20 subjects with T18, 88 subjects with T21, and 240 control subjects. There was no significant difference in age (T18: 4.6 [3.0-6. 9] vs. T21: 2.8 [1.9-4.0] vs. control: 2.9 [1.6-3.2] months, p = 0.06) and mean pulmonary arterial pressure (T18: 41 [33-49] vs. T21: 35 [30-41] vs. control: 36 [28-43] mmHg, p = 0.121) between the groups. The pulmonary to systemic blood flow ratio (Qp/Qs) (p = 0.983), Rp (p = 0.449), and Cp (p = 0.195) did not differ between T18 and control groups. However, Qp/Qs and Cp in T18 group were significantly greater than that in T21 group (T18: Qp/Qs: 3.4 [2.3-5.2] vs. T: 21 2.3 [1.7-3.7], p = 0.001. Cp: 3.5 [2.3-5.5] vs. 2.3 [1.6-3.1] mmHg/mL/m2 , p = 0.007), while Rp was identical between the groups (T18: 2.0 [1.6-3.3] vs. T21: 2.3 [1.7-3.7], p = 0.386). The pulmonary circulation in T18 subjects differed from that observed in T21 subjects, and identical to that observed in control subjects. Pulmonary hypertension is expected to be normalized after reasonable corrective surgery in T18 patients with congenital heart disease.

Coronary arterial dominance in patients with congenital heart disease.

Coronary arterial dominance is concerned in the management of ischemic heart disease. In particular, right coronary arterial dominance is having a risk for three-vessel coronary artery disease. Thus, this study aimed to explore coronary arterial dominance in patients with congenital heart disease. The study involved 250 patients, of which 105 patients were with tetralogy of Fallot (TOF), 100 patients with ventricular septal defect (VSD), and 45 patients with Kawasaki disease (KD). We retrospectively reviewed their ascending aortography to determine their coronary arterial dominance, Z-scores of coronary artery diameter, and the ascending aortic curvature, which pertained to the angle between the aortic annulus plane and ascending aortic plane. We identified relevant factors that contribute to having right coronary arterial dominance. Age and weight of the 250 subjects were 2.9 (1.0-8.7) months and 7.7 (5.0-9.4) kg, respectively. The Z-scores of right coronary and anterior descending arteries significantly differed among patients with TOF, VSD, and KD (P < 0.001, P = 0.001). However, there were no significant differences in the Z-scores of left main trunk and circumflex arteries. Right coronary arterial dominance occurred in 89%, 49%, and 61% in patients with TOF, VSD, and KD, respectively (P < 0.001). The presence of TOF was the most powerful predictor for right coronary arterial dominance (odds ratio: 10.31, 95% confidence interval: 4.11-27.2, P < 0.001). We found the robust relationship between right coronary arterial dominance and TOF. Patients with TOF may have an increased risk for the development of coronary artery disease during adulthood.

Distensibility of the ductus arteriosus in neonates and young infants undergoing transcatheter closure.

Device migration is one of serious complications in neonates and infants undergoing transcatheter closure of the patent ductus arteriosus (PDA). We hypothesize that neonates and young infants possess the distensibility of the ductus, which may be related to device migration. We retrospectively reviewed angiographic findings in 41 neonates and infants who underwent transcatheter closure of PDA. We measured diameters of the ductus at the pulmonary (PA) side, the center, and the aortic (AO) side before PDA closure, and the device center diameter after device closure. The distensibility index was defined as the ratio of the device center diameter after device deployment to the diameter at the center of the ductus before PDA closure. Age and weight at the procedure were 168 (117-260) days and 5.3 (4.3-6.9) kg, respectively. Thirty-seven subjects accomplished the successful device closure, and four subjects were declined because of the device instability or migration. Implanted devices included Amplatzer Duct Occluders in 33 subjects and Amplatzer Vascular Plug-2 in 8 subjects. The PDA diameters at PA side, at the center, AO side, and the device center diameter were 3.2 (2.2-4.3) mm, 4.7 (3.6-5.7) mm, 7.7 (6.3-9.4) mm, and 5.8 (4.2-6.9) mm, respectively. The PDA diameter before closure was not correlated age and weight. The distensibility index was 1.28 (1.06-1.64), which was significantly correlated to age (r = - 0.49, P = 0.001) and weight (r = - 0.53, P < 0.001). Infants with the younger age and the lower weight have the more distensible PDA, which may be a risk for device migration.

Long-Term Outcomes After an Individualized Strategy in Patients with Pulmonary Atresia and Intact Ventricular Septum.

This retrospective cohort study aimed to explore the long-term outcomes of an individualized strategy in patients with pulmonary atresia and intact ventricular septum (PAIVS). We analyzed survival and reintervention rates and identified risk factors for outcomes in patients with PAIVS treated based on individual right heart structures between 1979 and 2019. Ninety-five patients were included in this study. The z-scores of the pulmonary annulus, tricuspid annulus, and right ventricular end-diastolic volume were - 3.30 (- 15.15 to 1.83), - 0.70 (- 4.65 to 2.33), and - 1.51 (- 6.35 to 1.18), respectively. Right ventricular-dependent coronary circulation occurred in 15% of the patients. Among the 63 patients attempting biventricular strategy at first, 55 patients achieved biventricular circulation, 3 patients had one-and-a-half circulation, and 4 patients died perioperatively. Among the 33 patients attempting univentricular strategy at first, 10 patients died before the completion of Fontan operation, 17 patients (48%) accomplished Fontan operation, and 5 patients waited for Fontan operation. In one patient, conversion to biventricular circulation occurred. During the follow-up period of 720 person-years, the 20-year survival rate was significantly higher in patients with biventricular circulation than in those patients with univentricular circulation (93% vs. 67%, P < 0.001). Freedom from reintervention rates at 20 years was significantly lower in patients with biventricular circulation than in those patients with univentricular circulation (29% vs. 72%, P < 0.001). The pulmonary annulus z-score was an independent risk factor for reintervention in patients with biventricular circulation. Patients with biventricular circulation had an acceptable survival rate, but a high reintervention rate. Meanwhile, patients with univentricular circulation had high mortality before the completion of Fontan operation, although the reintervention rate was relatively low.

Focal segmental glomerulosclerosis in patients after Fontan operation: is this a Fontan-associated renal disease?

Despite acceptable survival for Fontan operation, there are concerns about late complications affecting the major organs. We herein present two cases of adults after Fontan operation who developed focal segmental glomerulosclerosis. These cases suggest that focal segmental glomerulosclerosis is owing to haemodynamic incompetence associated with Fontan operation, including congestion, hypoxia, and hyperviscosity, which may be called Fontan-associated renal disease.

Successful Mitral Valve Replacement in an Infant with Neonatal Marfan Syndrome due to a Novel Missense Mutation of the FBN1 Gene.

Marfan syndrome is an autosomal dominant genetic disorder of the fibrous connective tissue caused by pathogenic mutations in the fibrillin-1 gene. Neonatal Marfan syndrome is a rare type of Marfan syndrome that is genotypically and phenotypically different from classical Marfan syndrome and has a poor prognosis. Most patients with neonatal Marfan syndrome die during infancy due to severe and rapidly progressive cardiovascular disorders. Here, we present a case of an 11-year-old girl with neonatal Marfan syndrome due to a novel missense mutation in exon 27 of the fibrillin-1 gene. Her condition was critical due to progressive mitral and tricuspid regurgitation. Mitral valve replacement, performed at the age of 6 months, improved her critical condition. Our case suggests that early mitral valve replacement may lead to better outcomes in patients with neonatal Marfan syndrome.

Cerebral Insufficiency Caused by Diazoxide in a Premature Neonate with Congenital Hyperinsulinism.

Diazoxide is a peripheral vasodilator that has been used for intravenous treatment of hypertensive emergencies. However, it is currently used mainly for hyperinsulinemic hypoglycemia in lower dose orally, and its major side effects are edema and pulmonary hypertension. Herein, we report the first association between periventricular leukomalacia (PVL) and intractable hypotension due to diazoxide. A Japanese female premature infant showed hypoglycemia concomitant with hyperinsulinemia. She was diagnosed with congenital hyperinsulinism, and oral diazoxide was started. Six days after starting diazoxide, she suddenly showed peripheral coldness, oliguria, and severe hypotension. The hypotension was refractory to general vasopressor therapies and persisted even after the discontinuation of diazoxide. Cranial echography showed periventricular echodensities followed by cystic PVL. Low-dose vasopressin effectively treated the hypotension. This single case reminds us the serious adverse events of diazoxide that have been forgotten, especially in premature neonates.

Responses to Treatment According to the Cytokine Profiles of Pericardial Effusion in Two Children with Idiopathic Pericarditis.

Acute pericarditis is inflammation of the pericardium with or without pericardial effusion. In the pediatric population, most patients with acute pericarditis are diagnosed with idiopathic pericarditis. Herein, we present two children with idiopathic pericarditis who underwent immunological assessment of pericardial effusion for the first time. Both patients showed equally high levels of interleukin-6 in the pericardial effusion. However, they had different treatment responses, in accordance with the pericardial effusion and serum interleukin-10 concentrations. Our present cases suggest that interleukin-10 may be associated with the response to anti-inflammatory therapy in idiopathic acute pericarditis.

Distinct Distribution of Immunocytes in a Retropharyngeal Lymphadenopathy Associated with Kawasaki Disease: A Case Study Compared with Tonsillitis.

OBJECTIVES: Retropharyngeal lesions are often associated with Kawasaki disease (KD). A 4-year-old male first presented a peritonsillar and retropharyngeal abscess-like lesion. Surgical tonsillectomy was performed to avoid a risk of mediastinal abscess, but he fulfilled the diagnostic criteria of KD after the operation. This prompted us to perform a histological study on the KD tonsils. METHODS: The histopathology of the KD tonsil specimens were compared with hypertrophic tonsils obtained from 4 patients with chronic tonsillitis unrelated to KD assessed by the immunostainings. RESULTS: KD tonsils showed small lymphatic follicles and neutrophil infiltration in the peritonsillar muscle layer, with no evidence of vasculitis or abscess formation. The KD tonsils exclusively showed (1) predominant activated CD4+ T cells in the perifollicular interstitium, (2) sparse scattering of CD68+ monocytes/macrophages in the lymphatic follicles, and (3) polyclonal carcinoembryonic antigen-positive cells in the lymphatic follicles and venules with the high endothelial cells. CONCLUSIONS: The uniquely distributed immunocytes suggest the inflammatory process of KD involving the pathogen-associated molecules.

Case Report: Kawasaki disease associated with acute generalized exanthematous pustulosis secondary to carbocysteine.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption characterized by sterile pustules on an erythematous background, which is usually associated with drugs. AGEP is described as a self-limiting disease with favorable prognosis. We reported a case of Kawasaki Disease (KD) following AGEP. A 3-year-old male, who was admitted with pustules and five days of fever at our hospital, was diagnosed with AGEP. Despite the skin lesions and fever improving drastically after prednisolone therapy, the fever recurred on hospitalization day 5. The following symptoms suggestive of KD also appeared: bulbar conjunctival hyperemia, cervical lymphadenopathy, erythema of the lips, eruption on his trunk, and erythema and edema of the hands and feet. He was diagnosed with KD and treated with intravenous immunoglobulin. He was discharged on the thirteenth day of hospitalization without cardiac complications. Drug-induced lymphocyte stimulation test revealed carbocysteine as the suspected cause of AGEP, which consequently triggered KD. Because a mucosal lesion is uncommon in AGEP, bulbar conjunctival hyperemia suggested that KD sequentially occurred after AGEP. Since AGEP is benign and self-limited in most cases, it is necessary to differentiate other diseases, including KD, when recurrent fever or rash occurs in the course of AGEP.

Ultrasound and computed tomography findings of hepatic portal venous gas associated with acute appendicitis in a paediatric patient: A case report.

Introduction: Hepatic portal venous gas is a rare and life-threatening condition characterised by the presence of gas in the portal vein. Hepatic portal venous gas is frequently associated with intestinal ischaemia and necrosis. We present the case of a paediatric patient with acute appendicitis with hepatic portal venous gas detected using ultrasonography. Case report: A 5-year-old boy was admitted to our hospital with a respiratory tract infection. The boy started vomiting on day 2 of hospitalisation. He did not complain of any symptoms due to developmental retardation. We performed bedside point-of-care ultrasound, which detected hepatic portal venous gas, although the appendix could not be detected due to an acoustic shadow associated with bowel gas. Contrast-enhanced computed tomography revealed perforated appendicitis and pneumatosis intestinalis associated with paralytic ileus. An emergency laparoscopic appendectomy was performed. He was discharged on day 25 of hospitalisation after antibiotic therapy. Discussion: The present case suggests that the mechanism of hepatic portal venous gas was paralytic ileus, which caused gas-forming bacterial proliferation. The gas produced by bacteria and/or the gas-forming bacteria entered the bowel wall, which caused pneumatosis intestinalis. The bubbles in the intestinal wall floated in the portal system and were detected as hepatic portal venous gas. Perforated appendicitis and paralytic ileus seemed to be caused by a delayed diagnosis of appendicitis. The point-of-care ultrasound examination was useful for detecting hepatic portal venous gas and for helping establish the diagnosis of appendicitis. Conclusion: Hepatic portal venous gas is a rare finding associated with appendicitis in children. In addition, point-of-care ultrasound is useful for detecting hepatic portal venous gas in paediatric patients.

Intraindividual and interindividual variabilities in endogenous cortisol 6ß-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans.

This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22-58 years using endogenous cortisol 6ß-hydroxylation clearance [CLm(6ß)], a novel biomarker for CYP3A phenotyping. CLm(6ß) in the 49 healthy subjects was 2.40 ± 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 ± 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 ± 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6ß) in 14 healthy subjects in the morning at 10:00-12:00 every 2 or 3 days over a period of 36-53 days and observed a 1.5-fold to 3.4-fold day-to-day intraindividual variability in the CYP3A activity. The mean value for CLm(6ß) in each subject for 36-53 days was 2.54 ± 0.76 ml/min (n = 14). We also evaluated the CLm(6ß) every 2 hours from 8:00-20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 ± 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A.

Separation and quantitative determination of 6α-hydroxycortisol and 6ß-hydroxycortisol in human urine by high-performance liquid chromatography with ultraviolet absorption detection.

The present study developed an high-performance liquid chromatography (HPLC) method for the simultaneous determination of urinary metabolites of endogenous cortisol, 6α-hydroxycortisol (6α-OHF) and 6ß-hydroxycortisol (6ß-OHF), in human urine, using 6α-hydroxycorticosterone as internal standard. 6α-OHF and 6ß-OHF were extracted from urine with ethyl acetate by using a Sep-Pak C(18) plus cartridge. Separation of the stereoisomers was achieved on a reversed-phase hybrid column by a gradient elution of (A) 0.05 M KH(2)PO(4)-0.01 M CH(3)COOH (pH 3.77) and (B) 0.05 M KH(2)PO(4)-0.01 M CH(3)COOH/acetonitrile (2:3, v/v). 6α-OHF and 6ß-OHF were well separated on an XTerra MS C(18) 5 µm column using two types of stepwise gradient elution program (programs 2 and 3). Resolutions of 6α-OHF and 6ß-OHF were Rs = 4.41 for program 2 and Rs = 4.60 for program 3. The analysis was performed within 23~26 min, monitored by UV absorbance at 239 nm. The lower limits of detection of 6α-OHF and 6ß-OHF were 0.80 ng per injection (s/n = ca. 8), and the lower limits of quantification were 5.02 ng/ml for 6α-OHF and 41.08 ng/ml for 6ß-OHF, respectively. The within-day reproducibilities in the amounts of 6α-OHF and 6ß-OHF determined were in good agreement with the actual amounts added, the relative errors being -5.37% and -3.73% (gradient 2) and -5.69% and -3.96% (gradient 3) for both 6α-OHF and 6ß-OHF, respectively. The inter-assay precisions (RSDs) for 6α-OHF and 6ß-OHF were less than 1.99% (gradient 2) and 2.61% (gradient 3), respectively. The present HPLC method was applied to the measurement of 6α-OHF and 6ß-OHF in urine to evaluate the time courses of 6α-hydroxylation and 6ß-hydroxylation clearances of cortisol during 40 days for phenotyping CYP3A in a healthy subject.

Being Overweight Is Related to Neoaortic Sinus Dilatation After Arterial Switch Operation.

BACKGROUND: Neoaortic sinus dilatation is a late comorbidity after an arterial switch operation in patients with dextro-transposition of the great arteries. We aim to explore whether neoaortic sinus dilatation is related to overweight or obesity, as these affect aortic remodeling in such patients. METHODS: We measured neoaortic diameters including those for the annulus, sinus, sinotubular junction, and ascending aorta by echocardiography and studied the relationship between these diameters and body mass index in patients aged 15 years and older after an arterial switch operation. RESULTS: A total of 45 patients were studied. Median (interquartile range) age, body mass index, and systolic blood pressure at echocardiography were 20 (17-28) years, 21.2 (18.4-24.2) kg/m2, and 120 (112-127) mm Hg, respectively. Echocardiogram revealed the following median values (interquartile ranges): neoaortic annulus diameter, 22.2 (19.8-23.8) mm; sinus diameter, 34.6 (31.8-39.8) mm; sinotubular junction diameter, 27.5 (22.4-30.0) mm; and ascending aortic diameter, 20.4 (19.4-22.7) mm. The neoaortic sinus diameter was significantly correlated with body mass index (r = 0.41, P = .004) and was significantly larger in patients with concomitant ventricular septal defect (P < .001) and those who were over-weight (body mass index ≥25 kg/m2; P = .006). CONCLUSION: Neoaortic sinus dilatation after an arterial switch operation is associated with being overweight during adolescence and young adulthood. It is important to prevent obesity in patients after an arterial switch operation and educate them on a healthy lifestyle.

Safety and Feasibility of Infliximab Therapy in Children With Kawasaki Disease Who Received Live Vaccinations.

BACKGROUND: Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear. METHODS: We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated. RESULTS: Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines. CONCLUSIONS: Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration.

Overgrowth of the Amygdala in Children with Single Ventricle Congenital Heart Disease.

Aim: Early life stress is associated with overgrowth of the amygdala, which plays a key role in the processing and memory of emotional responses. Herein, we aimed to explore the amygdala volume in children with single-ventricle congenital heart disease who experience repeated admissions during the neonatal period and infancy. Methods: We compared the amygdala volume measured using brain magnetic resonance imaging (MRI) between 40 patients after completion of the Fontan procedure and 40 age- and sex-matched control subjects Results: Age at the MRI study were 9.2 (8.5-11.1) and 10.2 (9.2-10.3) years in the Fontan and control groups, respectively. The maximum amygdala volume in the Fontan group was significantly larger than in the control group (1232 [983-1392] mm3/m2 vs. 980 [728-1166] mm3/m2, P < 0.001). The amygdala volume did not correlate to cardiac index (r = 0.260) and central venous pressure (r = -0.107) in the Fontan group. Conclusions: Children with single-ventricle congenital heart disease exhibited amygdala overgrowth.

Metabolism and disposition of isoflavone conjugated metabolites in humans after ingestion of kinako.

Isoflavone aglycones daidzein (Dein) and genistein (Gein) are present primarily as glucuronides and sulfates in human plasma; however, very little is known about the plasma pharmacokinetics of isoflavone conjugates after soy ingestion. The aim of this study was to investigate metabolism and disposition of the isoflavone conjugated metabolites glucuronide or sulfate or both after ingestion of kinako (baked soybean flour) by 10 volunteers. The quantifications of 16 metabolites in plasma and urine were performed by our previously reported high-performance liquid chromatography-UV-diode-array detector method. Plasma concentrations of total Dein and Gein metabolites reached maximal values of 0.64 ± 0.18 µM at 4.7 ± 2.5 h and 1.58 ± 0.55 µM at 5.4 ± 2.1 h, respectively. The area under the curve from 0 to 48 h demonstrated that daidzein-7-glucuronide-4'-sulfate (D-7G-4'S) (53.3%) was a major metabolite of Dein and that genistein-7-glucuronide-4'-sulfate (G-7G-4'S) (54.0%) and genistein-4',7-diglucuronide (G-4',7-diG) (26.6%) were major metabolites of Gein in plasma. The compositions of isoflavone metabolites in urine and plasma were greatly different. Approximately half of the 48-h urinary excretion of total Dein metabolites consisted of daidzein-7-glucuronide. The total amounts of genistein-7-glucuronide and genistein-4'-glucuronide were half the total amount of the urinary Gein metabolites. Excretion into urine of D-7G-4'S and G-7G-4'S accounted for only 16% each of the total Dein and Gein metabolites, respectively. The plasma and urine profiles of 16 metabolites of Dein and Gein demonstrate the involvement of desulfation and deglucuronidation of the conjugated metabolites D-7G-4'S, G-7G-4'S, and G-4',7-diG in the process of renal excretion.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

BACKGROUND AND OBJECTIVES: Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. METHODS: Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. RESULTS: The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. CONCLUSION: In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Identification and quantification of daidzein-7-glucuronide-4'-sulfate, genistein-7-glucuronide-4'-sulfate and genistein-4',7-diglucuronide as major metabolites in human plasma after administration of kinako.

Much attention has been paid to the metabolism and disposition of isoflavones daidzein (Dein) and genistein (Gein) with regard to the prevention of several hormone-dependent diseases. Recent studies have reported that several conjugates as well as aglycones may be biologically active or may be activated within target cells. However, the disposition of Dein and Gein in plasma is still uncertain. This paper describes the identification and quantification of the highly polar metabolites, daidzein-7-glucuronide-4'-sulfate (D-7G-4'S), genistein-7-glucuronide-4'-sulfate (G-7G-4'S), daidzein-4',7-diglucuronide (D-4',7-diG), and genistein-4',7-diglucuronide (G-4',7-diG) in human plasma after dietary administration of kinako (baked soybean powder) to two healthy volunteers. The structure identification of these conjugated metabolites in plasma was performed in comparison to the LC-ESI-MS and 600 MHz (1)H-NMR spectral data of the chemically synthesized compounds. Furthermore, 16 isoflavone metabolites including D-7G-4'S, G-7G-4'S, D-4',7-diG, and G-4',7-diG in plasma were simultaneously measured by a high-performance liquid chromatography-UV-diode-array detector method combined with solid-phase extraction using an Oasis HLB cartridge. D-7G-4'S, G-7G-4'S and G-4',7-diG were found to be major metabolites of Dein and Gein in plasma, while intact aglycones were detected to be only ca. 2% in both subjects. The findings suggest that the conjugated metabolites could be the key compounds responsible for pharmacological and medicinal properties of isoflavones.