Combinatorial interpretation of BMP and WNT controls the decision between primitive streak and extraembryonic fates.

BMP signaling is essential for mammalian gastrulation, as it initiates a cascade of signals that control self-organized patterning. As development is highly dynamic, it is crucial to understand how time-dependent combinatorial signaling affects cellular differentiation. Here, we show that BMP signaling duration is a crucial control parameter that determines cell fates upon the exit from pluripotency through its interplay with the induced secondary signal WNT. BMP signaling directly converts cells from pluripotent to extraembryonic fates while simultaneously upregulating Wnt signaling, which promotes primitive streak and mesodermal specification. Using live-cell imaging of signaling and cell fate reporters together with a simple mathematical model, we show that this circuit produces a temporal morphogen effect where, once BMP signal duration is above a threshold for differentiation, intermediate and long pulses of BMP signaling produce specification of mesoderm and extraembryonic fates, respectively. Our results provide a systems-level picture of how these signaling pathways control the landscape of early human development.

Identification of signature gene set as highly accurate determination of metabolic dysfunction-associated steatotic liver disease progression.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat accumulation in the liver. MASLD encompasses both steatosis and MASH. Since MASH can lead to cirrhosis and liver cancer, steatosis and MASH must be distinguished during patient treatment. Here, we investigate the genomes, epigenomes, and transcriptomes of MASLD patients to identify signature gene set for more accurate tracking of MASLD progression. METHODS: Biopsy-tissue and blood samples from patients with 134 MASLD, comprising 60 steatosis and 74 MASH patients were performed omics analysis. SVM learning algorithm were used to calculate most predictive features. Linear regression was applied to find signature gene set that distinguish the stage of MASLD and to validate their application into independent cohort of MASLD. RESULTS: After performing WGS, WES, WGBS, and total RNA-seq on 134 biopsy samples from confirmed MASLD patients, we provided 1,955 MASLD-associated features, out of 3,176 somatic variant callings, 58 DMRs, and 1,393 DEGs that track MASLD progression. Then, we used a SVM learning algorithm to analyze the data and select the most predictive features. Using linear regression, we identified a signature gene set capable of differentiating the various stages of MASLD and verified it in different independent cohorts of MASLD and a liver cancer cohort. CONCLUSION: We identified a signature gene set (i.e., CAPG, HYAL3, WIPI1, TREM2, SPP1, and RNASE6) with strong potential as a panel of diagnostic genes of MASLD-associated disease.

Meibomian Gland Dysfunction in Primary Acquired Nasolacrimal Duct Obstruction.

This study was designed to investigate the influence of primary nasolacrimal duct obstruction (PANDO) on the structure and function of the Meibomian gland and to examine whether it is related to functional failure after dacryocystorhinostomy surgery. Medical records of patients diagnosed as PANDO from August 2021 to February 2022 were retrospectively studied. Results of slit lamp examination, lacrimal drainage test, tear break-up time, anterior segment optical coherence tomography, and meibography were collected. Tear meniscus height, tear break-up time, meiboscore, and lipid layer thickness of tear membrane were parameters compared between the eyes with complete PANDO and the control group. Medical records of 44 patients, therefore 88 eyes were collected, and there were 28 eyes with complete PANDO (total obstruction group), while normal eyes (control group) were 30. Mean tear meniscus height was significantly higher than that of the control group ( P value<0.001), but tear break-up time ( P value=0.322), lipid layer thickness ( P value=0.755), and meiboscore ( P value=0.268) were not significantly different. However, in the cases with moderate and severe meibomian gland destruction, the lipid layer thickness of the total obstruction group was significantly thinner than the control group. Lipid secretion of meibomian glands was less in eyes with PANDO than in eyes without PANDO, under moderate to severe meibomian gland destruction. It can lead to persistent epiphora after dacryocystorhinostomy due to a compensatory response against evaporative dry eye disease. Patients should be educated before the decision to undergo surgeries about the possibilities of persistent epiphora. Further studies are needed to prove the mechanism of meibomian gland function disturbance in PANDO.

Longitudinal Changes in Peripapillary and Macular Vessel Densities in Glaucomatous Eyes With a Single-Hemifield Retinal Nerve Fiber Layer Defect.

PRCIS: The peripapillary vessel density decreased significantly in the affected hemiretina compared with that in the intact hemiretina in glaucomatous eyes with a single-hemifield retinal nerve fiber layer defect. PURPOSE: To evaluate the difference in the change rates of peripapillary vessel density (pVD) and macular vessel density (mVD) measured using optical coherence tomography angiography (OCTA) in glaucomatous eyes with a single-hemifield retinal nerve fiber layer (RNFL) defect. MATERIALS AND METHODS: We performed a retrospective, longitudinal study of 25 patients with glaucoma who were followed up for at least 3 years, with a minimum of 4 visits after baseline OCTA. At each visit, all participants underwent OCTA examination, and the pVD, mVD were measured by removing the large vessels. Changes in the pVD, mVD, peripapillary RNFL thickness (pRNFLT), and macular ganglion cell inner plexiform layer thickness were investigated in the affected and intact hemispheres, and the differences between the 2 hemispheres were compared. RESULTS: In the affected hemiretina, the pVD, mVD, pRNFLT, and mCGIPLT were reduced than that in the intact hemiretina (all, P < 0.001). The changes in pVD and mVD were statistically significant at the 2-year and 3-year follow-ups in the affected hemifield (all, P <0.05). However, pVD and mVD did not show statistically significant changes in the intact hemiretina throughout the follow-up visits. Although the pRNFLT decreased significantly at the 3-year follow-up, the macular ganglion cell inner plexiform layer thickness showed no statistical change at any follow-up visit. Compared with the intact hemisphere, pVD was the only parameter that showed significant changes throughout the follow-up period. CONCLUSION: Although pVD and mVD decreased in the affected hemiretina, the reduction in pVD was significant compared with that in the intact hemiretina.

Causes of Tearing in Patients With Chemotherapy: Meibomian Gland Dysfunction Versus Lacrimal Drainage Obstruction.

Numerous ocular toxicities that have been associated with the use of chemotherapeutic agents present as problems with the ocular surface, ocular adnexa, and lacrimal system, and many chemotherapeutic agents have tearing as a side effect. In this study, 34 eyes from 17 patients with a mean age of 62.4±14.8 years were analyzed. Chemotherapy was administered for a mean of 13.8±7.6 months. Chemotherapeutic agents of the following types were included: titanium silicate-1 (58.8%), Docetaxel (23.5%), Paclitaxel (11.8%), and 5-fluorouracil (5.9%). Tearing began 9.1 to 10.9 months after chemotherapy treatment. Within 3 months of beginning chemotherapy, tearing occurred in 9 patients (52.9%), and within 6 months, it occurred in 11 patients (64.7%). Mean tear break-up time was 5.4±2.6 sec. Ten eyes (29.4%) had normal fluorescein dye disappearance test findings (within grade 1), and the mean fluorescein dye disappearance test was 1.91±0.87. Among the 34 eyes, 24 (70.6%) had normal puncta and 9 (26.5%) and 1 (2.9%) had stenosis and blockage, respectively. Ten eyes (29.4%) showed total regurgitation, 19 eyes (55.9%) showed partial regurgitation, and 5 eyes (14.7%) showed no regurgitation upon syringing. Four eyes (11.8%) and 30 eyes (88.2%), respectively, showed soft and hard stops upon probing. Dacryoscintigraphy confirmed that 6 eyes (17.6%) were normal, 8 eyes (23.5%) showed post-sac delay or obstruction, and 20 eyes (58.8%) showed pre-sac delay or obstruction. The mean meiboscores for the upper and lower eyelids on LipiView were 2.15±0.86 and 2.53±0.79, respectively. The difference in meiboscores between the upper and lower eyelids was significant ( P=0.004 ). Obstruction of the lacrimal drainage system is a significant contributing factor to tearing in chemotherapy patients. However, reflex tearing because of meibomian gland dysfunction should also be fully considered to effectively manage the tearing because of the high incidence of accompanying meibomian glands loss when the lacrimal drainage system is obstructed.

Anterior Segment Optical Coherence Tomography for Canaliculitis.

Canaliculitis is an uncommon inflammation of the lacrimal canaliculi, and it is often misdiagnosed as conjunctivitis or dacryocystitis. There are no gold-standard methods to diagnose canaliculitis, therefore newer methods such as ulrasound biomicroscopy are being introduced. Anterior segment optical coherence tomography (OCT) is being utilized to evaluate punctum and canaliculus, but no previous study has applied anterior OCT for canaliculitis. One case of canaliculitis with canaliculith was diagnosed by anterior segment OCT noninvasively, by successful detection of canaliculith. Pouting of the punctum and detection of canaliculith as hyper-reflective signals by OCT were checked, which was impossible with other conventional methods. Surgical incision and drainage confirmed the presence of stones. This article is meaningful as a first study about the diagnosis of canaliculitis with canaliculith using anterior segment OCT. Presence of canaliculith in vertical canaliculus, and the status of punctal epithelium and canalicular mucosa was possible in this study.

Changes in Lower Eyelid Positions After Blepharoplasty and Levator Advancement Surgery.

PURPOSE: To investigate changes in the upper and lower eyelid positions using information from before and immediately after surgery in patients who underwent upper blepharoplasty and ptosis surgery. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of patients who underwent upper blepharoplasty with a diagnosis of dermatochalasis and patients who underwent levator advancement or levator resection with a diagnosis of congenital or aponeurotic ptosis. The marginal reflex distance 1 (MRD1), marginal reflex distance 2 (MRD2), palpebral fissure height (PFH), and operation time were also investigated. RESULT: In the dermatochalasis group, the preoperative mean MRD1, MRD2, and PFH were 1.94±1.27, 4.71±0.95, and 6.65±1.65 mm, respectively. Mean MRD1, MRD2, and PFH values immediately after surgery were 1.80±0.79, 4.22±0.90, and 6.02±1.34 mm, respectively. In the ptosis group, the preoperative mean MRD1, MRD2, and PFH values were 0.27±1.34, 5.73±1.13, and 5.99±1.94 mm, respectively. Postoperative mean MRD1, MRD2, and PFH were 1.76±1.13, 4.22±1.01, and 5.98±1.60 mm, respectively. CONCLUSIONS: It is important to remember that MRD2 could decrease during surgery. Therefore, to prevent overcorrection after upper eyelid surgery, MRD1 (not the overall PFH) should be considered to determine the appropriate extent of surgery during the procedure.

Effects of Hyaluronic Acid/Collagen Resorbable Gel Use in Endoscopic Dacryocystorhinostomy.

The purpose of this study was to investigate whether the use of hyaluronic acid/collagen resorbable gel (Regenwel®) has an inhibitory effect on rhinostomy obstruction during endoscopic dacryocystorhinostomy (Endo DCR). A total of 298 patients diagnosed with unilateral primary acquired nasolacrimal duct obstruction from May 2017 to June 2021 who underwent Endo DCR were enrolled. The patients were divided into the Regenwel group (152 patients) and the Control group (146 patients) that did not use Regenwel during surgery, and the medical records were compared and analyzed retrospectively. The mean age of the Regenwel group was 65.8 years, and that of the Control group was 63.2 years. Regarding anatomical success as the primary outcome, the Regenwel group had a higher success rate than the Control group (96.7% vs 86.3%, P = .012), and the functional success result confirmed that the Regenwel group had a higher success rate than the Control group (94.1% vs 84.3%, P = .024). Among secondary outcomes, granulation formation occurred less frequently in the Regenwel group than in the Control group (9.2% vs 32.2%, P < .001), and there was no statistically significant difference in postoperative bleeding between the 2 groups (0% vs 1.4%, P = .478). The Regenwel group had fewer infections after surgery than the Control group (5.3% vs 8.9%, P = .012) and required less frequent revision surgery (2.0% vs 15.8%, P < .001). In conclusion, Regenwel is a resorbable gel containing hyaluronic acid and collagen that is used during Endo DCR and is thought to contribute to the improvement of surgical success rate by preventing complications such as rhinostomy obstruction and bleeding after surgery.

Hypoglycemic and Hypolipogenic Action of Acetic Acid and Monascus-Fermented Grain Vinegar: A Comparative Study.

Acetic acid has been proposed to improve lifestyle-related diseases, including hyperlipidemia and hyperglycemia. This study compared the hypoglycemic and hypolipogenic effects of acetic acid vinegar (AV, contains only 4% acetic acid) and Monascus-fermented grain vinegar (MV) containing various bioactive compounds in 3T3L1 cells and C57BL/KsJ-db/db mice (DB). The DB were divided randomly into three treatment groups containing nine mice each; DB-, AV-, and MV-groups were orally administered 1 mL/kg/day of distilled water, acetic acid vinegar, and Monascus vinegar, respectively, for 8 weeks. Exposure to AV and MV inhibited the adipogenic differentiation of 3T3L1 preadipocytes and lipid accumulation during differentiation. Oral administration of AV or MV to the mice resulted in a marked reduction in the body weight, liver weight, and hepatic triglyceride content compared to the control DB-group. Moreover, treatment with AV and MV clearly increased the expression of cyclic adenosine monophosphate (cAMP) and AMP-activated protein kinase (AMPK) and suppressed the expression of fatty acid synthetase in liver tissues of DB. Significantly, lower levels of fasting blood glucose, insulin, leptin, and the glycosylated hemoglobin (HbA1c) as well as higher levels of the skeletal muscle GLUT4 expression were obtained in the AV- or MV-groups than levels determined in the control DB-group (P < .05). Although MV has the potential to be a natural alternative treatment for obesity-associated type 2 diabetes, this study suggests that acetic acid is the central ingredient in MV responsible for the hypoglycemic and hypolipogenic effects in the DB mice.

Diagnostic clues of IOP pulsation on applanation tonometry in carotid-cavernous fistula patients.

BACKGROUND: Carotid-cavernous fistula (CCF) is an abnormal communication between the cavernous sinus and the carotid arterial system and exhibits typical symptoms of red eye, diplopia, blurred vision, headache, and murmur. However, the symptoms for CCF may vary and can lead to misdiagnosis. IOP pulsations provide a hint leading to suspicion of CCF. We report three cases related to CCF differential diagnosis: two cases of CCF patients and one case of conjunctivitis with corkscrew conjunctival vessels. CASE PRESENTATION: The case 1 patient, with a typical unilateral CCF, exhibited significant IOP pulsation in Goldmann tonometry measurements in the affected eye. The case 2 patient did not show typical symptoms of CCF except asymmetric upper eyelid swelling (right > left). In clinical evaluation, IOP elevation in the right eye and IOP pulsation in both eyes were noted. Based on radiology, the patient was diagnosed with bilateral CCF. The case 3 patient was referred to our institution for differential diagnosis of CCF. The patient had corkscrew conjunctival vessels in both eyes, which had appeared after he had been revived through CPR (cardiopulmonary resuscitation) 25 years prior. IOP pulsation was not observed in Goldmann tonometry. Radiology test result for arterio-venous fistula was negative in the case 3 patient. CONCLUSION: For diagnosis of CCF, IOP pulsation by Goldmann applanation tonometry exhibits a good correlation with the disease in our cases and provides useful diagnostic clues.

Intraoperative Significance of Lower Eyelid Positions in Levator Advancement to Prevent Overcorrection.

PURPOSE: The purpose of this study was to investigate changes in the position of the upper and lower eyelids before and immediately after surgery in patients that underwent ptosis surgery. METHODS: The authors retrospectively reviewed the clinical records of patients diagnosed with congenital or aponeurotic ptosis and that were treated with levator advancement with local anesthesia. The marginal reflex distance 1 (MRD1), marginal reflex distance 2 (MRD2), and palpebral fissure height (PFH) were measured using clinical photographs. RESULT: The preoperative mean MRD1, MRD2, and PFH were 0.27 ± 1.34 mm, 5.73 ± 1.13 mm, and 5.99 ± 1.94 mm, respectively. The postoperative mean MRD1, MRD2, and PFH were 1.76 ± 1.03 mm, 4.22 ± 1.01 mm, and 5.98 ± 1.60 mm, respectively. The postoperative MRD1 was significantly increased and postoperative MRD2 was decreased significantly compared to preoperative values (both, P < 0.001). The preoperative and postoperative PFH values were not significantly different ( P = 0.941). CONCLUSIONS: It is important to assess the degree of reverse ptosis before surgery in patients that undergo ptosis surgery, and to remember that MRD2 and PFH may be reduced during surgery. Therefore, the position of the upper eyelid should be intraoperatively adjusted based on MRD1, not the PFH, to prevent overcorrection after surgery.

Clinical Manifestations in Patients Wearing Ocular Prostheses.

PURPOSE: This study aimed to assess upper and lower eyelid shapes and changes in patients wearing ocular prostheses. METHODS: The authors retrospectively reviewed the clinical records of patients wearing ocular prostheses. Clinical manifestations, including superior sulcus deepening, ptosis, upper and lower eyelid entropion, upper and lower eyelid ectropion, upper and lower eyelid retraction, and upper and lower eyelid socket contracture were investigated. RESULTS: For those patients who underwent evisceration, the most common clinical manifestations of the eyelid were superior sulcus deepening and ptosis (35%, respectively), whereas lower eyelid entropion and lower eyelid retraction were the second most common manifestations (25%, respectively). Among those patients who underwent enucleation, the most common eyelid changes were lower eyelid entropion (45.5%), and ptosis and lower eyelid socket contracture were the second most common alterations (36.4%, respectively). Finally, superior sulcus deepening, upper eyelid entropion, and lower eyelid retraction occurred in 27.3% of patients, respectively. CONCLUSIONS: Upper eyelid ptosis, superior sulcus deepening, and lower eyelid entropion and retraction were the most common clinical manifestations in patients wearing ocular prostheses. When following up with patients with ocular prostheses, it is important to check these eyelid changes and consider making appropriate corrections.

Increase of central foveal and temporal choroidal thickness in patients with inactive thyroid eye disease.

BACKGROUND: In this study, we aimed to compare the choroidal thickness between a group of Korean patients with inactive thyroid eye disease (TED) and a control group of Korean patients and to analyze the variables affecting choroidal thickness. METHODS: Patients diagnosed with inactive TED and without TED who underwent optical coherence tomography and axial length measurements were included and classified into the TED group and control group. Choroidal thickness was measured using images acquired in enhanced depth imaging (EDI) mode by cirrus HD-OCT (Carl Zeiss Meditec Inc., Dublin, CA, UAS) at the central fovea and points 1.5 mm nasal and 1.5 mm temporal from the central fovea using a caliper tool provided by OCT software. RESULTS: The mean central foveal choroidal thickness was 294.2 ± 71.4 µm and 261.1 ± 47.4 µm in the TED and control groups, respectively, while the mean temporal choroidal thickness was 267.6 ± 67.5 µm and 235.7 ± 41.3 µm in the TED and control groups, respectively, showing significant differences between the two groups (P = 0.011, P = 0.008). The mean nasal choroidal thickness was 232.1 ± 71.7 µm and 221.1 ± 59.9 µm in the TED and control groups, respectively, showing no significant difference between the two groups (P = 0.421). Multivariate regression analysis showed the factors affecting central foveal choroidal thickness were age, axial length, and degree of exophthalmos, and factors affecting temporal choroidal thickness were age and degree of exophthalmos. CONCLUSIONS: Central foveal and temporal choroidal thickness were significantly thicker in patients with inactive TED than in control subjects, while age, axial length, and degree of exophthalmos were identified as major factors affecting choroidal thickness.

Urinary metabolic markers reflect on hepatic, not intestinal, CYP3A activity in healthy subjects.

Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.

The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects.

Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6ß-OH-cortisone/cortisone and plasma 4ß-OH-cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI.

From genome sequencing to the discovery of potential biomarkers in liver disease.

Chronic liver disease progresses through several stages, fatty liver, steatohepatitis, cirrhosis, and eventually, it leads to hepatocellular carcinoma (HCC) over a long period of time. Since a large proportion of patients with HCC are accompanied by cirrhosis, it is considered to be an important factor in the diagnosis of liver cancer. This is because cirrhosis leads to an irreversible harmful effect, but the early stages of chronic liver disease could be reversed to a healthy state. Therefore, the discovery of biomarkers that could identify the early stages of chronic liver disease is important to prevent serious liver damage. Biomarker discovery at liver cancer and cirrhosis has enhanced the development of sequencing technology. Next generation sequencing (NGS) is one of the representative technical innovations in the biological field in the recent decades and it is the most important thing to design for research on what type of sequencing methods are suitable and how to handle the analysis steps for data integration. In this review, we comprehensively summarized NGS techniques for identifying genome, transcriptome, DNA methylome and 3D/4D chromatin structure, and introduced framework of processing data set and integrating multi-omics data for uncovering biomarkers. [BMB Reports 2020; 53(6): 299-310].

Development of a Korean-specific virtual population for physiologically based pharmacokinetic modelling and simulation.

Physiologically based pharmacokinetic (PBPK) modelling and simulation is a useful tool in predicting the PK profiles of a drug, assessing the effects of covariates such as demographics, ethnicity, genetic polymorphisms and disease status on the PK, and evaluating the potential of drug-drug interactions. We developed a Korean-specific virtual population for the SimCYP® Simulator (version 15 used) and evaluated the population's predictive performance using six substrate drugs (midazolam, S-warfarin, metoprolol, omeprazole, lorazepam and rosuvastatin) of five major drug metabolizing enzymes (DMEs) and two transporters. Forty-three parameters including the proportion of phenotypes in DMEs and transporters were incorporated into the Korean-specific virtual population. The simulated concentration-time profiles in Koreans were overlapped with most of the observed concentrations for the selected substrate drugs with a < 2-fold difference in clearance. Furthermore, we found some drug models within the SimCYP® library can be improved, e.g., the minor allele frequency of ABCG2 and the fraction metabolized by UGT2B15 should be incorporated for rosuvastatin and lorazepam, respectively. The Korean-specific population can be used to evaluate the impact of ethnicity on the PKs of a drug, particularly in various stages of drug development.

Development of a physiologically-based pharmacokinetic model for cyclosporine in Asian children with renal impairment.

This study aimed to assess the pharmacokinetics of cyclosporine A (CsA) in Asian children with renal impairment (RI) by developing a physiologically-based pharmacokinetic (PBPK) model with Simcyp Simulator. The PBPK model of Asian children with RI was developed by modifying the physiological parameters of the built-in population libraries in Simcyp Simulator. The ratio of healthy and RI populations was obtained for each parameter showing a difference between the populations. Each ratio was multiplied by the corresponding parameter in healthy Asian children. The model verification was performed with published data of Korean children with kidney disease given multiple CsA administrations. Simulations were performed with different combinations of ethnicity, age, and renal function to identify the net impact of each factor. The simulated results suggested that the effect of RI was higher in children than adults for both Caucasian and Asian. In conclusion, the constructed model adequately characterized CsA pharmacokinetics in Korean children with RI. Simulations with populations categorized by ethnicity, age, and renal function enabled to assess the net impact of each factor on specific populations.

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment.

BACKGROUND: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4ß-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. METHODS: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6ß-OH-cortisol/cortisol, 6ß-OH-cortisone/cortisone, 4ß-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4ß-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. RESULTS: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone as well as plasma 4ß-OH-cholesterol and 4ß-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. CONCLUSION: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.