Biliary Clearance Research Articles

Interplay of Drug Metabolism and Transport: A Real Phenomenon or an Artifact of the Site of Measurement?

The interdependence of both transport and metabolism on the disposition of drugs has recently gained heightened attention in the literature, and has been termed the "interplay of transport and metabolism". Such "interplay" is observed when inhibition of biliary clearance of a drug results in an "apparent" increase in the metabolic clearance of the drug or vice versa. In this manuscript, we derived and explored through simulations a physiological-based pharmacokinetic model that integrates both transport and metabolism and explains the "apparent" dependence of hepatic clearance on both these processes. In addition, we show that the phenomenon of hepatic "transport-metabolism interplay" is a result of using the plasma concentration as a point of reference when calculating metabolic or biliary clearance, and this interplay is maximal when the drug is actively transported into the hepatocytes (i.e., hepatocyte sinusoidal influx clearance is greater than the sinusoidal efflux clearance). When the hepatic drug concentration is used as a reference point to calculate metabolic or biliary clearance, this interplay ceases to exist. A mechanistic understanding of this interplay phenomenon can be used to explain the somewhat paradoxical results that may be observed in drug-drug interaction studies when a drug is cleared by both metabolism and biliary excretion. That is, when one of these two pathways is inhibited, the other pathway appears to be induced or activated. This interplay results in an increase in hepatic drug concentrations and therefore has implications for the hepatic efficacy and toxicity of a drug.

Nuclear Medicine Hepatobiliary Imaging

Nuclear medicine hepatobilary imaging (HIDA) is a time proven imaging methodology that uses radioactive drugs and specialized cameras to make imaging diagnoses based on physiology. HIDA radiopharmaceuticals are extracted by hepatocytes in the liver and cleared through the biliary system similar to bilirubin. The most common indication for HIDA imaging is acute cholecystitis, diagnosed by nonfilling of the gallbladder due to cystic duct obstruction. HIDA can detect high grade biliary obstruction prior to ductal dilatation; images reveal a persistent hepatogram without biliary clearance due to the high backpressure. HIDA also aids in the diagnosis of partial biliary obstruction due to stones, biliary stricture, and sphincter of Oddi obstruction. It can confirm biliary leakage postcholecystectomy and hepatic transplantation. Calculation of a gallbladder ejection fraction after cholecystokinin infusion is commonly used to diagnose chronic acalculous gallbladder disease. Diseased gallbladders do not contract. There are many other less common but valuable diagnostic indications for HIDA imaging.

Biliary efflux transporters involved in the clearance of rosuvastatin in sandwich culture of primary rat hepatocytes

Rosuvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) has been shown to be excreted mostly unchanged into the bile; interactions on the level of hepatic apical efflux transporters may represent a risk of liver toxicity. So far, controversial and insufficient data are available concerning transporters involved in the elimination process. This study was designed to elucidate, which transporters take part in the biliary clearance of rosuvastatin using sandwich-cultured primary rat hepatocytes. The canalicular efflux of rosuvastatin was measured in the presence of inhibitors: Ko 134, mitoxanthrone, novobiocin for breast cancer resistance protein (Bcrp); verapamil for multidrug resistance protein (Mdr1); benzbromarone, sulfasalazine, probenecid for multidrug resistance associated protein (Mrp 2); and cyclosporine A, glibenclamide, troglitazone for bile salt export pump (Bsep). Mrp2 inhibitors decreased the biliary efflux of rosuvastatin most potently by 78.9%, 35%, 54.1%; benzbromarone, probenecid, sulfasalazine, respectively, while Bcrp and Bsep inhibitors showed much less effect (29.1%, 23.0% ,30.0%; Ko 134, mitoxanthrone, novobiocin, respectively, and 32.6%, 29.3%, 20.6%, glibenclamide, cyclosporine A, troglitazone, respectively). The marked decline of canalicular transport by Mrp2 inhibitors suggests major role of Mrp2 in this process; however, Bcrp and Bsep might also contribute to the biliary elimination of rosuvatatin in sandwich-cultured rat hepatocytes.

Lenalidomide-Induced Hepatotoxicity: A Case Report

Purpose: Lenalidomide is an immunomodulatory drug increasingly used for the treatment of patients with multiple myeloma and myelodysplastic syndromes. There is little data on hepatotoxicity related to this medication. We present a case of lenalidomide induced hepatotoxicity. Methods: A 67-year-old African-American male with known IgG lambda multiple myeloma was hospitalized with jaundice, fatigue, and vomiting. Patient was receiving second 3 week course of lenalidomide 25 mg orally daily, and dexamethasone 40 mg orally daily, when his symptoms appeared and progressively worsened during the 2nd week trial of therapy, resulting in hospitalization. When admitted, patient was found to be febrile (T-max 38.6 C) and have hyperbilirubinemia (peak value 4.4 g/dl) with direct biluribin predominance (peak value 3.3 g/dl). There was elevation of alkaline phosphatase (190 u/l), AST (145 u/l), and ALT (139 u/l). Concern for cholangitis was raised and antibiotic treatment initiated. Patient was also noted to have worsening of his chronically impaired kidney function (peak creatinine of 3.4 mg/dl). Imaging studies including abdominal ultrasound and subsequent MRCP revealed no cholelithiasis, normal caliber bile ducts without filling defects, and no other abnormalities. Hepatobiliary scan showed abnormal gallbladder ejection fraction and delayed biliary tract radio-isotope clearance. Patient was not receiving other hepatotoxic medications and serology was negative for viral hepatitis. Lenalidomide was considered to be potential cause of liver function tests abnormalities and this medication was discontinued. Consequently, hyperbilirubinemia normalized within the next 4 days. Other liver function tests also declined. Patient was found to have urinary tract infection thought to have caused the fever (resolved rapidly after initiating the antibiotic). Kidney impairment was established to be pre-renal, due to dehydration of nausea and vomiting. Renal function returned to baseline (creatinine of 1.7 mg/dl) with hydration. The patient improved clinically with described treatment allowing discharge 8 days after the initial presentation. Discussion: Coincidence of liver function impairment with lenalidomide treatment and discontinuation suggests possible hepatotoxic effect of this medication clinically presenting as cholestasis. Lenalidomide is mainly excreted by the kidneys and patients with reduced renal function may be at risk for related hepatotoxicity. Altered renal function and cholestatic presentation was also present in one of the other 2 published cases of lenalidomide related hepatotoxicity. Conclusion: Physicians should be aware of potential hepatotoxicity related to lenalidomide use, especially in patients with renal impairment.

Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport

Hepatocellular accumulation of bile acids due to inhibition of the canalicular bile salt export pump (BSEP/ ABCB11) is one proposed mechanism of drug-induced liver injury (DILI). Some hepatotoxic compounds also are potent inhibitors of bile acid uptake by Na +-dependent taurocholate cotransporting polypeptide (NTCP/ SLC10A1). This study used a cassette dosing approach in rat and human sandwich-cultured hepatocytes (SCH) to determine whether known or suspected hepatotoxic drugs inhibit bile acid transport individually or in combination. [ 3H]-Taurocholate served as the NTCP/BSEP probe substrate. Individually, cyclosporin A and rifampin decreased taurocholate in vitro biliary clearance (Cl biliary) and biliary excretion index (BEI) by more than 20% in rat SCH, suggesting that these drugs primarily inhibited canalicular efflux. In contrast, ampicillin, carbenicillin, cloxacillin, nafcillin, oxacillin, carbamazepine, pioglitazone, and troglitazone decreased the in vitro Cl biliary by more than 20% with no notable change in BEI, suggesting that these drugs primarily inhibited taurocholate uptake. Cassette dosing ( n = 2–4 compounds per cassette) in rat SCH yielded similar findings, and results in human SCH were consistent with rat SCH. In summary, cassette dosing in SCH is a useful in vitro approach to identify compounds that inhibit the hepatic uptake and/or excretion of bile acids, which may cause DILI.

Up-regulation of renal Mdr1 and Mrp2 transporters during amiodarone pretreatment in rats

Although amiodarone (AMD) is known to produce drug–drug interactions through inhibition of transporter-mediated excretion of drugs, its impact on these mechanisms during chronic treatment has not been described yet. Therefore, the aim of this study was to investigate the influence of AMD pretreatment on the main multidrug transporting proteins, Mdr1 and Mrp2, in the liver and kidney. The expression of the transporters and pharmacokinetics of their substrates, rhodamine-123 (Rho123) and endogenous conjugated bilirubin (CB), were evaluated in rats after either AMD oral pretreatments (4–14 days) or single intravenous bolus. AMD pretreatment of all durations up-regulated renal Mdr1 and Mrp2 protein expression to 155–190% and 152–223% of the control values, respectively. In agreement, we observed a corresponding increase in renal clearance of both substrates. Hepatic expression was increased only for Mdr1 to 234–270% of controls, which was associated with increased biliary elimination of amiodarone without change in Rho123 biliary clearance. Interestingly, hepatic expression of another Mdr transporter, Mdr2, was progressively decreased by amiodarone administration. Acute administration of AMD reduced Rho123 biliary clearance by 64%. Our results indicate that repeated administration of AMD to rats is associated with significant increase in hepatic and renal expression of Mdr1 and Mrp2 transporters, which may contribute to variability in pharmacokinetics of AMD and simultaneously applied drugs.

Effect of St John’s wort on the disposition of fexofenadine in the isolated perfused rat liver

This study examined the effects of St John's wort (Hypericum perforatum) on the disposition of fexofenadine, a substrate of P-glycoprotein/organic anion transporting polypeptide, in the isolated perfused rat liver. Male Sprague-Dawley rats were given St John's wort, 1000 mg/kg, by intragastric gavage once daily for 14 days. On day 15, livers were isolated surgically and perfused in a recirculating system with fexofenadine (2 microg/ml), either alone or following addition of ciclosporin (0.5 microg/ml) 5 min before the addition of fexofenadine. Perfusate samples and bile were collected for 60 min. Fexofenadine in perfusate, bile and the homogenised livers was measured by HPLC. Administration of St John's wort significantly increased biliary clearance with respect to perfusate and biliary clearance with respect to the concentration in the liver, by 74% and 71%, respectively. This was reversed by ciclosporin. St John's wort enhanced the elimination of fexofenadine into the bile. This could be because it increases the activity of P-glycoprotein on the canalicular membrane of hepatocytes.

Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure-pharmacokinetic relationships (QSPKR) to predict biliary clearance (CL(b)) and percentage of administered dose excreted in bile as parent drug (PD(b)) in rats and humans. CL(b) and PD(b) data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PD(b). Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PD(b) for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CL(b) showed a significant correlation (R (2) = 0.819) with good prediction performance (Q (2) = 0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CL(b) in rats and PD(b) data for anions or cation/neutral compounds in rats and humans. Both CL(b) and PD(b) data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.

Quantitative Expression Profile of Hepatobiliary Transporters in Sandwich Cultured Rat and Human Hepatocytes

As sandwich cultured (SC) hepatocytes can repolarize to form bile canalicular networks, allowing active excretion of compounds in a vectorial manner, the model has been widely used for assessing the transporter related complexity of ADME/tox issues. A lack of quantitative information on transporter expression during cell culture has made in vitro to in vivo extrapolation of hepatobiliary transport difficult. In the present study, using our newly developed LC-MS/MS absolute quantitative methods, we determined the quantitative expression profile of three biliary transporters in SC rat and human hepatocytes. A significant shift of hepatobiliary transporter proteins was observed both in human and rat sandwich cultures. A decrease of BSEP/Bsep protein and an increase of BCRP/Bcrp protein were detected in both rat and human hepatocytes over time in culture. Interestingly, Mrp2 in rat hepatocytes was significantly diminished, while MRP2 constantly increased in human hepatocytes during the cell culture. Consequently, the interspecies difference between rat and human in absolute amount of MRP2/Mrp2 was minimized over time in culture. Following the sandwich culture, the species difference of hepatobiliary transporter protein between human and rat at day 5 post SC was diminished (MRP2/Mrp2), identical (BSEP/Bsep) or reversed (BCRP/Bcrp), compared to the in vivo situation. In addition, the absolute protein amount of BCRP/Bcrp or MRP2/Mrp2 was proportionally correlated with the intrinsic biliary clearance estimated in various lots of SC rat and human hepatocytes. The results revealed that absolute protein amount is a key determinant for hepatobiliary clearance and could provide fundamental support on extrapolation of biliary secretion from in vitro to in vivo.

Association of the c.3972C>T Variant of the Multidrug Resistance-Associated Protein 2 Gene (MRP2/ABCC2) with Susceptibility to Bile Duct Cancer

Background: Multidrug resistance-associated protein 2 (MRP2/ABCC2) is one of the ATP-binding cassette (ABC) transporters expressed on the apical membrane of hepatocytes and cholangiocytes. ABCC2 plays an important role in the biliary clearance of endogenous and exogenous toxic compounds. Recently, the ABCC2 variant c.3972C>T in exon 28 has been shown to be associated with hepatocellular carcinoma risk. Our aim was to assess the role of this ABCC2 variant on cholangiocarcinoma susceptibility. Methods: Prospectively, we recruited 60 cholangiocarcinoma patients and 73 healthy controls of Caucasian origin. The c.3972C>T polymorphism was genotyped using solution-phase hybridization reactions with 5′-nuclease and fluorescence detection (TaqMan assays). Results: Allele frequencies were in Hardy-Weinberg equilibrium (p > 0.05). The c.3972T allele was significantly more frequent in patients with cholangiocarcinoma (39.2%) compared to healthy controls (26.0%, p = 0.022), resulting in an odds ratio (OR) of 1.83 (95% CI = 1.09–3.08). Armitage’s trend test showed a significant association between genotypes and cancer susceptibility (p = 0.026, OR = 1.95). Conclusions: We describe a novel association between the common ABCC2 variant c.3972C>T and cholangiocarcinoma risk. Further studies are warranted to replicate our findings in different populations and to elucidate the mechanisms of this observation.

Biliary clearance of bromosulfophthalein in anesthetized and freely moving conscious rat

The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization compared with conscious rats. These results demonstrate that the pharmacokinetics of BSP, including biliary clearance, in ketamine or Zoletil anesthetized rats is virtually identical to that in conscious rats and it may be related to blood flow limited hepatic disposition of BSP. Furthermore, they suggest the conscious rat model does not offer methodological advantage and the anesthesia model is suitable for a realistic approximation of the hepatobiliary transport of BSP.

Hepatobiliary Disposition of Thyroid Hormone in Mrp2-Deficient TR− Rats: Reduced Biliary Excretion of Thyroxine Glucuronide Does Not Prevent Xenobiotic-Induced Hypothyroidism

The hepatobiliary disposition of thyroxine (T4) was evaluated in Groningen Yellow transport deficient (TR(-)) rats lacking functional multidrug resistance-associated protein 2 (Mrp2; Abcc2). Male Wistar and TR(-) rats were dosed orally (4 days) with phenobarbital (PB; 100 mg/kg) or DMP 904 (200 mg/kg), after which T4 homeostasis and hepatic cytochromes P450, UDP-glucuronosyltransferase, xenobiotic transporters, and T4 glucuronidation were determined. Serum concentrations of T4 were approximately 50% higher in control TR(-) rats than Wistars. PB and DMP 904 increased hepatic levels of P450s and T4-glucuronidation (T4-G), and these changes were associated with decreased serum T4 levels in both strains. In Wistar but not TR(-) rats, DMP 904 increased thyroid stimulating hormone levels twofold. Hepatobiliary clearance of T4 was determined after intravenous infusion of [(125)I]T4 to rats dosed with PB and DMP 904 (4 days). PB and DMP 904 increased plasma clearance and hepatic uptake of [(125)I]T4 equivalents in Wistar but not TR(-) rats. Total biliary clearance (Cl(bile)) was approximately 0.85 and 0.2 ml/h in Wistar and TR(-) rats, respectively, with virtually no T4-G excreted in bile in TR(-) rats. Biliary clearance of unconjugated T4 was also lower in control TR(-) rats than in Wistars, although DMP 904 increased its biliary clearance in both strains. These results suggest that Mrp2 is likely to be responsible for biliary excretion of T4-G and contributes in part to excretion of T4. Decreased biliary clearance of T4 and metabolites in TR(-) rats mitigated but did not prevent drug-induced changes in serum T4, suggesting that other factors contribute to changes in T4 homeostasis in these rats.

Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

Multidrug-resistant protein 2 (MRP2/ABCC2), expressed on the canalicular membrane of hepatocytes, mediates the secretion of conjugated or nonconjugated compounds into bile and plays an important role in physiology and drug elimination. A heterocyclic compound, BPCPU [1-(1-(4-bromophenyl)-3-carbamoyl-1H-pyrazol-4-yl) urea], which was metabolically stable in vitro in rat liver microsomes and freshly isolated rat hepatocytes, demonstrated a saturable nonlinear pharmacokinetic profile in the rat. Polarized efflux was observed for this compound in Caco-2 cells, with a low K(m) = 1.06 +/- 0.06 microM. The Caco-2 efflux was dose-dependent and saturable. Coadministration of 25 microM MK571 ([3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid]), an MRP inhibitor, blocked the polarized efflux in Caco-2 cells. In contrast, this compound did not inhibit calcein efflux in MRP2 gene-transfected Madin-Darby canine kidney cells, suggesting that it is a substrate, not an inhibitor, of the MRP2/ABCC2 transporter. To investigate the mechanism for the nonlinear pharmacokinetics, bile duct-cannulated rats were used to obtain time profiles of plasma concentration, biliary, and urinary excretion after intravenous administration at various doses. The plasma clearance increased remarkably with decreased dose, from 1.5 ml/min/kg at 5 mg/kg to 14.9 ml/min/kg at 0.05 mg/kg. A dose-dependent biliary excretion also was observed. The results revealed that saturation of hepatobiliary secretion played a role in the dose-dependent changes in total body clearance and biliary clearance. Saturating concentrations of the Mrp2/Abcc2 substrate, BPCPU, causing decreased hepatobiliary clearance could be the major cause for the nonlinear pharmacokinetics observed in rats.

Alteration of Methotrexate Biliary and Renal Elimination during Extrahepatic and Intrahepatic Cholestasis in Rats

Methotrexate (MTX), an important anticancer and immunosuppressive agent, has been suggested for the treatment of primary biliary cirrhosis. However, the drug's pharmacodynamics and toxicity is dependent on its concentrations in plasma which in turn are directly related to MTX's elimination in the liver and kidney. Therefore, the aim of this study was to evaluate changes in MTX biliary and renal excretion during either intrahepatic or obstructive cholestasis in rats. The steady state pharmacokinetic parameters of MTX were evaluated in rats one (BDO1) or seven (BDO7) days after bile duct obstruction (BDO) or 18 h after administration of lipopolysaccharide (LPS). In comparison to the respective control groups, biliary and total clearances of MTX were decreased to 12% and 49% in the BDO1 group, to 5% and 56% in the BDO7 animals, and to 42% and 43% in the LPS group, respectively. Renal clearance of MTX was unchanged in BDO groups, but decreased to 23% of controls in the LPS animals. The serum biochemistry and expression of main hepatic MTX transporters (Mrp2, Mrp3, Mrp4, Bcrp, Oatp1a1, Oatp1a4 and Oatp1b2) confirmed the pathological cholestatic changes in the liver and partly elucidated the cause of changes in MTX pharmacokinetic parameters. In conclusion, this study is the first describing marked alteration of MTX hepatic and renal elimination induced by cholestasis in rats. Moreover, the reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models.

Effects of Intestinal Ischemia/Reperfusion on P-Glycoprotein Mediated Biliary and Renal Excretion of Rhodamine123 in Rat

To analyze the effects of I/R on P-gp function in liver and kidney, biliary and urinary excretions of rhodamine123 as a substrate of P-gp were examined in rats. The effects of reperfusion time on change and recovery of P-gp function were also examined. The biliary and renal clearance of rhodamine123 significantly decreased at 3 hr after reperfusion, but returned to control levels at 24 hr after reperfusion. These results suggest that intestinal I/R-induced decrease in P-gp-mediated biliary and renal excretion of rhodamine123 is litely due to impairment of P-gp-mediated transport ability. The level of P-gp protein in liver decreased and that of iNOS mRNA increased at 3 hr after reperfusion and both levels returned to control levels at 24 hr after reperfusion. No marked change in the levels of P-gp protein and iNOS mRNA was observed in kidney at 3 hr and 24 hr after reperfusion. Thus, decrease in biliary excretion of rhodamine123 would appear due in part to decrease in expression of P-gp, caused by increase in lipid peroxidation levels through iNOS mRNA.

Use of Sandwich-Cultured Human Hepatocytes to Predict Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors

Use of Sandwich-Cultured Human Hepatocytes to Predict Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors

Bromosulfophthalein의 체내동태 평가에 미치는 분석법의 영향: HPLC 법과 UV 흡광광도법의 비교

The aim of this study was to evaluate the difference of analytical methods for the pharmacokinetic study of bromosulfophthalein (BSP), an indicator of hepatobiliary function. The plasma and bile concentrations of BSP after intravenous administration were measured according to custom UV spectroscopy and HPLC, respectively. Plasma concentration of BSP measured by UV spectroscopy was similar to that measured by HPLC. There was no significant difference in the distribution volume, total body clearance, area under the curve and mean residence time of BSP between different analytical method groups. However, bile concentration of BSP measured by UV spectroscopy was overestimated compared with concentration measured by HPLC method. Biliary clearance of BSP obtained from UV spectroscopy method was almost 3 times higher than that obtained from HPLC method. Thus, a feasibility of UV spectroscopy method for high throughput pharmacokinetic evaluation of BSP was limited to the study based on the plasma concentration of BSP, not bile concentration.

Use of Sandwich-Cultured Human Hepatocytes to Predict Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors

Previous reports have indicated that in vitro biliary clearance (Cl(biliary)) determined in sandwich-cultured hepatocytes correlates well with in vivo Cl(biliary) for limited sets of compounds. The purpose of this study was 1) to determine the in vitro Cl(biliary) in sandwich-cultured human hepatocytes of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism and 2) to compare the predicted Cl(biliary) values with estimated in vivo hepatic clearance data in humans. The average biliary excretion index and in vitro intrinsic Cl(biliary) values of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin in sandwich-cultured human hepatocytes were 35, 23, 31, 25, and 16%, respectively, and 0.943, 1.20, 0.484, 3.39, and 5.48 ml/min/kg, respectively. Cl(biliary) values predicted from sandwich-cultured human hepatocytes correlated with estimated in vivo hepatic clearance values based on published data (no in vivo data in humans was available for pitavastatin), and the rank order was also consistent. In conclusion, in vitro Cl(biliary) determined in sandwich-cultured human hepatocytes can be used to predict in vivo Cl(biliary) of compounds in humans.

Radiopharmaceutical Agents for Myocardial Perfusion Imaging

Myocardial perfusion imaging (MPI) is a well-established noninvasive method of assessing coronary blood flow.1–5 MPI is capable of identifying regional abnormalities in coronary artery blood flow and determining their physiological relevance to myocardial function and viability. MPI requires the intravenous injection of a radioactive blood flow marker followed by imaging of regional myocardial uptake.6–10 Imaging is most frequently performed by tomographic techniques (ie, SPECT [single-photon emission computerized tomography]) with electrocardiographically synchronized image gating. Used frequently in conjunction with either physical exercise or pharmacological stress, MPI is useful in unmasking myocardial perfusion deficits not evident at rest. A thorough discussion of clinical indications for MPI is beyond the scope of this review, but the reader is referred to recently published consensus committee documents.11,12 Three radioactive blood flow markers (RBFMs) are clinically available and in widespread use: (1) thallium Tl 201 chloride, (2) technetium Tc-99m sestamibi (Cardiolite; Lantheus Medical Imaging, North Billerica, Mass), and (3) technetium Tc-99m tetrofosmin (Myoview; GE Healthcare, Princeton, NJ). In the present review, these agents will be referred to by their nonproprietary names. The oldest of the 3 RBFMs, thallium 201, has been in use since approximately 1980, and the original experimental and clinical validation studies of MPI were performed with this agent.1,13–16 More recently, 99mTc-labeled sestamibi, approved in 1990, and tetrofosmin, approved in 1995, have been developed and validated clinically.6–8,17,18 In comparative imaging studies analyzed for accuracy (sensitivity, specificity, and normalcy rates), no obvious differences have been found among these 3 agents. Each RBFM has unique properties that determine the logistics of its use and its test performance characteristics. The purpose of the present review is to compare and contrast these 3 RBFMs. It is hoped this detailed overview will assist clinicians in choosing which agent(s) to use and in understanding …

Endoscopic treatment of choledochal cyst type III

BACKGROUND: Todani type III cysts are not very common disease. Endoscopically the choledochocele is not a challenging diagnosis. Sometimes biliary stone disease is associated and events of cholangitis and pancreatitis may occur. Normally these patients are referred for surgical treatment, mainly because there is a widespread concept that choledocal cysts are very prone to develop neoplasia and must be resected. Nevertheless surgical resection is not free of morbidity. The chance for neoplasia in such cases seems to be related to the presence of pancreaticobiliary reflux towards the common bile duct. AIM: To report a case of endoscopic treatment of choledochal cyst type III with literature review. CASE REPORT: Young man with recurrent abdominal pain, fever and hyperamylasemia. An ERCP showed pancreaticobiliary maljunction and calculus impaction. Papillotomy was performed and complete biliary clearance was achieved. Amylase contents in the common bile duct was measured and normal. Due to absence of pancreatiobiliary reflux, a second endoscopic approach was performed and a wide communication between choledochocele and duodenum was done with diathermy (using the papillotome). The patient recovering was uneventful and in 30 months follow-up he remains asymptomatic. CONCLUSION: Since pancreatobiliary reflux is not present, surgical approach of the diverticulum seemed to be not necessary. Endoscopic drainage of choledococele was a good option for conservative treatment.