Predictors and Clinical Outcomes of Fibroid Expulsion After Uterine Artery Embolization.

PURPOSE: To evaluate rates of fibroid expulsion after uterine artery embolization (UAE) and risk factors. MATERIALS AND METHODS: Single-center retrospective study of UAEs for fibroids between 2016 and 2020. Preoperative UAE and patients with incomplete follow-up were excluded. Patients underwent MRI before and 3 months after UAE and/or as indicated. Medical records were reviewed, and patient demographics, fibroid characteristics and clinical events were recorded. Fibroid expulsion included fibroid exposure to the endometrial cavity on MRI, and tissue loss/passage as observed clinically or on MRI. Symptoms were considered major if requiring additional clinic visits or treatment. Statistical tests included Chi-square, Fisher's exact test, and logistic regression models. RESULTS: One hundred ninety-nine women were included. Symptomatic fibroid expulsion occurred after 31 (16%) procedures: 16 minor and 15 major. Symptoms included vaginal discharge (n = 23), bleeding (n = 9), tissue passage (n = 9), cramping/pain (n = 3), and fever (n = 4). Fifteen women (8%) needed additional care, of whom 6 (3%) required invasive procedures (4 elective hysterectomies, 1 hysteroscopic resection, 1 transvaginal removal of passing tissue). The International Federation of Gynecology and Obstetrics (FIGO) classification was significantly associated with symptomatic fibroid expulsion (p = 0.001). Odds ratio for symptomatic expulsion and expulsion requiring additional care for FIGO 3-7 versus 0-2 fibroids was 0.32 (95% confidence interval, 0.14-0.71, p = 0.005) and 0.28 (95% confidence interval, 0.10-0.83, p = 0.02), respectively. Other factors were not consistently associated with expulsion. CONCLUSION: Fibroid expulsion after uterine artery embolization was more common than previously reported but mostly asymptomatic or minimally symptomatic. Women with FIGO ≤ 2 fibroids should be appropriately counseled regarding risk for expulsion.

Consensus minimum core data elements adapted to peripheral vascular intervention in the drug-eluting era: Consensus report from the Registry Assessment of Peripheral Interventional Devices (RAPID) Pathways "LEAN" working group.

Registry Assessment of Peripheral Interventional Devices (RAPID) initiated the Pathways Program to provide a transparent, collaborative forum in which to pursue insights into multiple unresolved questions on benefit-risk of paclitaxel-coated devices, including understanding the basis of the mortality signal, without a demonstrable potential biological mechanism, and whether the late mortality signal could be artifact intrinsic to multiple independent prospective randomized data sources that did not prespecify death as a long-term end point. In response to the directive, the LEAN-Case Report Form working group focused on enhancements to the RAPID Phase I Minimum Core Data set through the addition of key clinical modifiers that would be more strongly linked to longer-term mortality outcomes after peripheral arterial disease intervention in the drug-eluting device era, with the goal to have future mortality signals more accurately examined.

Bridging Hepatocellular Carcinoma to Transplant: Transarterial Chemoembolization Response, Tumor Biology, and Recurrence after Transplantation in a 12-Year Transplant Cohort.

PURPOSE: To evaluate tumor response to transarterial chemoembolization as well as biologic characteristics of the tumor as predictors of recurrence after transplantation in patients with hepatocellular carcinoma (HCC) who were bridged or down-staged to liver transplantation. MATERIALS AND METHODS: An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant, single-institution retrospective analysis was performed on all patients with HCC who were treated with the use of conventional transarterial chemoembolization or transarterial chemoembolization with drug-eluting embolics (DEE) over a 12-year period and who subsequently underwent liver transplantation (n = 142). Treatment response was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) imaging criteria and then correlated with tumor characteristics and recurrence. Of the 142 patients followed after transplantation, 127 had imaging after transarterial chemoembolization but before transplantation. Imaging response and post-transplantation recurrence were correlated with patient demographics, liver function, and tumor morphology. HCC recurred in 9 patients (mean time from transplantation, 526 days). Recurrence was analyzed with the use of univariate and multivariate statistics. Kaplan-Meier recurrence-free survival curves were calculated based on immediate imaging response before transplantation with the use of the log-rank test. RESULTS: Before transplantation, 57% of patients (72/127) demonstrated complete response (CR) and 24% (31/127) showed partial response (PR). Complete pathologic necrosis occurred in 54% (39/72) of CR patients and 20% (6/31) of PR patients. Poor treatment response, defined as stable disease (SD) or progressive disease (PD), occurred in 18% of patients (24/127) before transplantation and was present in 67% of cases of recurrence (6/9; P < .001). Post-transplantation recurrence was present in 1.4% of patients (1/71) with CR and in 6.5% of patients (2/31) with PR. In patients with SD after transarterial chemoembolization, HCC recurred in 18.8% of transplant patients (3/16) and in 43% of patients (3/7) with PD. Larger pretreatment tumor size (P = .05), higher Child-Pugh score (P = .002), higher tumor grade at explantation (P = .04), and lymphovascular invasion at explantation (P = .008) also were associated with increased incidence of post-transplantation recurrence. CONCLUSIONS: Poor tumor response to transarterial chemoembolization before transplantation identifies patients at increased risk for post-transplantation recurrence.

Comparison of Cone-Beam Tomography and Cross-Sectional Imaging for Volumetric and Dosimetric Calculations in Resin Yttrium-90 Radioembolization.

PURPOSE: To compare the use of cone-beam computed tomography versus contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) in the calculation of liver volume and planned dose for yttrium-90 radioembolization. MATERIALS AND METHODS: The study retrospectively assessed 47 consecutive patients who underwent resin Y-90 radioembolization consecutively over a 2-year period at a single center. Volume calculation software was used to determine perfused lobar liver volumes from cone-beam CT (CBCT) images obtained during mapping angiography. CBCT-derived volumes were compared with perfused lobar volume derived from contrast-enhanced CT and MRI. Nominal activities as determined by the SIR-Spheres Microspheres Activity Calculator were similarly calculated and compared using both CBCT and conventionally acquired volumes. RESULTS: A total of 82 hepatic lobes were assessed in 47 patients. The mean percentage difference between combined CT-MRI- and CBCT-derived calculated lobar volumes was 25.3% (p = 0.994). The mean percentage difference in calculated dose between the two methods was 21.8 ± 24.6% (p = 0.42). Combined left and right lobar CT-derived dose difference was less than 10% in 22 lobes, between 10 and 25% in 20 lobes, between 25 and 50% in 13 lobes and greater than 50% in 5 lobes. Combined left and right lobar MRI-derived dose difference was less than 10% in 11 lobes, between 10 and 25% in 7 lobes, between 25 and 50% in 2 lobes and greater than 50% in 1 lobe. CONCLUSIONS: Although volume measurements derived from CT/MRI did not differ significantly from those derived from CBCT, variability between the two methods led to large and unexpected differences in calculated dose.

Treatment of bile acid amidation defects with glycocholic acid.

UNLABELLED: Bile acid amidation defects were predicted to present with fat/fat soluble vitamin malabsorption with minimal cholestasis. We identified and treated five patients (one male, four females) from four families with defective bile acid amidation due to a genetically confirmed deficiency in bile acid CoA:amino acid N-acyl transferase (BAAT) with the conjugated bile acid, glycocholic acid (GCA). Fast atom bombardment-mass spectrometry analysis of urine and bile at baseline revealed predominantly unconjugated cholic acid and absence of the usual glycine and taurine conjugated primary bile acids. Treatment with 15 mg/kg GCA resulted in total duodenal bile acid concentrations of 23.3 ± 19.1 mmol/L (mean ± SD) and 63.5 ± 4.0% of the bile acids were secreted in bile in the conjugated form, of which GCA represented 59.6 ± 9.3% of the total biliary bile acids. Unconjugated cholic acid continued to be present in high concentrations in bile because of partial intestinal deconjugation of orally administered GCA. Serum total bile acid concentrations did not significantly differ between pretreatment and posttreatment samples and serum contained predominantly unconjugated cholic acid. These findings confirmed efficient intestinal absorption, hepatic extraction, and biliary secretion of the administered GCA. Oral tolerance tests for vitamin D2 (1,000 IU vitamin D2/kg) and tocopherol (100 IU/kg tocopherol acetate) demonstrated improvement in fat-soluble vitamin absorption after GCA treatment. Growth improved in 3/3 growth-delayed prepubertal patients. CONCLUSION: Oral glycocholic acid therapy is safe and effective in improving growth and fat-soluble vitamin absorption in children and adolescents with inborn errors of bile acid metabolism due to amidation defects.

Reduction of the body burden of PCBs and DDE by dietary intervention in a randomized trial.

Serum polychlorinated biphenyls (PCBs) in Anniston, AL, residents have been associated with hypertension and diabetes. There have been no systematic interventions to reduce PCB body burdens in Anniston or other populations. Our objective was to determine the efficacy of 15 g/day of dietary olestra to reduce PCBs in Anniston residents. Blood PCBs and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene were measured at baseline and 4-month intervals in a double-blind, placebo-controlled, 1-year trial. Participants with elevated serum PCBs were randomized into two groups of 14 and received potato crisps made with olestra or vegetable oil (VO). Elimination rates during the study period were compared with 5-year prestudy rates. Eleven participants in the olestra group and 12 in the VO group completed the study. Except for one participant in the VO group, reasons for dropout were unrelated to treatments. The elimination rate of 37 non-coplanar PCB congeners during the 1-year trial was faster during olestra consumption compared to the pretrial period (-0.0829 ± 0.0357 and -0.00864 ± 0.0116 year(-1), respectively; P=.04), but not during VO consumption (-0.0413 ± 0.0408 and -0.0283 ± 0.0096 year(-1), respectively; P=.27). The concentration of PCBs in two olestra group participants decreased by 27% and 25% during the trial. There was no significant time by group interaction in change from baseline. However, group main effects for total PCBs and PCB 153 were of borderline significance. This pilot study has demonstrated that olestra can safely reduce body burdens of PCBs and supports a larger intervention trial that may also determine whether reduction in PCBs will reduce the risk of hypertension and diabetes.

Effect of dietary sphingomyelin on absorption and fractional synthetic rate of cholesterol and serum lipid profile in humans.

BACKGROUND: Diets enriched with sphingolipids may improve blood lipid profiles. Studies in animals have shown reductions in cholesterol absorption and alterations in blood lipids after treatment with sphingomyelin (SM). However, minimal information exists on effect of SM on cholesterol absorption and metabolism in humans. The objective was to assess the effect of SM consumption on serum lipid concentrations and cholesterol metabolism in healthy humans. METHODS: Ten healthy adult males and females completed a randomized crossover study. Subjects consumed controlled diets with or without 1 g/day SM for 14 days separated by at least 4 week washout period. Serum lipid profile and markers of cholesterol metabolism including cholesterol absorption and synthesis were analyzed. RESULTS: Serum triglycerides, total, LDL- and VLDL- cholesterol were not affected while HDL cholesterol concentrations were increased (p = 0.043) by SM diet consumption. No change in cholesterol absorption and cholesterol fractional synthesis rate was observed with supplementation of SM compared to control. Intraluminal cholesterol solubilization was also not affected by consumption of SM enriched diet. CONCLUSIONS: In humans, 1 g/day of dietary SM does not alter the blood lipid profile except for an increased HDL-cholesterol concentration and has no effect on cholesterol absorption, synthesis and intraluminal solubilization compared to control. TRIAL REGISTRATION: Clinicaltrials.gov # NCT00328211.

Decreased plasma cholesterol concentrations after PUFA-rich diets are not due to reduced cholesterol absorption/synthesis.

Plasma cholesterol concentrations increase with consumption of high saturated fatty acid (SFA) and decrease with high polyunsaturated fatty acid (PUFA) diets, leading to shifts in lipid levels consistent with reduction in heart disease risk. Direct measurements of cholesterol absorption, one of the key regulators of plasma cholesterol levels, have not been performed in humans after consumption of high PUFA diets. Thus, cholesterol absorption and fractional synthesis rates (FSRs) were measured in 16 healthy adults (8 males and 9 females) using a randomized cross-over study with a diet containing high (PUFA/SFA) P/S ratio (2:1) and a low P/S ratio (0.5:1). Cholesterol absorption and fractional cholesterol synthetic rates were measured using stable isotopes after 20 days of dietary intervention. Diet did not affect cholesterol absorption or synthesis. There was a significant decrease in plasma cholesterol concentrations (P < 0.02), specifically LDL-cholesterol (P < 0.02), without a change in HDL-cholesterol or triacylglycerol concentrations. Intraluminal cholesterol solubilization and plasma sterol (cholesterol biosynthetic intermediates and plant sterols) levels were not affected by diet. Thus, consumption of diets with a high P/S ratio reduces plasma total and LDL-cholesterol concentrations independent of shifts in cholesterol absorption or synthesis.

Fat malabsorption in cystic fibrosis: comparison of quantitative fat assay and a novel assay using fecal lauric/behenic acid.

OBJECTIVES: The gold standard for the diagnosis of fat malabsorption, the 72-hour fat balance study, requires a 3-day collection to generate a coefficient of fat absorption (CFA). We hypothesized that a new test using behenic acid (behenate test) as a nonabsorbable lipid marker may provide a facile means to assess fat absorption. The study proposed to answer 2 questions: first, whether the behenate test correlated with the gold standard and, second, whether the CFA improved when taking pancreatic enzymes during meals instead of taking them before meals. PATIENTS AND METHODS: The study compared the behenate test with the gold standard in 15 patients with cystic fibrosis during 3 arms that require 3- to 4-day hospitalization: first, taking pancreatic enzymes before meals; second, taking it during meals; and third, without taking it. RESULTS: The mean CFA was 78.3% when pancreatic enzymes were taken during meals and 80.4% when these enzymes were taken before meals. Correlation between the CFA and the behenate test for collections during all 3 arms was r = 0.219 (P = 0.001). CONCLUSIONS: Timing of ingestion of pancreatic enzymes does not significantly alter the CFA. Although the CFA correlates with the behenate test, the correlation is not robust enough to justify replacement of the gold standard by this test. It is unclear whether the poor correlation between tests relates to intermeal variability in fat excretion or other factors; however, the behenate test may be suitable as a screening test for the detection of fat malabsorption.

Role of human pregnane X receptor in tamoxifen- and 4-hydroxytamoxifen-mediated CYP3A4 induction in primary human hepatocytes and LS174T cells.

Previously we observed that the antiestrogens tamoxifen and 4-hydroxytamoxifen (4OHT) induce CYP3A4 in primary human hepatocytes and activate human pregnane X receptor (PXR) in cell-based reporter assays. Given the complex cross-talk between nuclear receptors, tissue-specific expression of CYP3A4, and the potential for tamoxifen and 4OHT to interact with a myriad of receptors, this study was undertaken to gain mechanistic insights into the inductive effects of tamoxifen and 4OHT. First, we observed that transfection of the primary cultures of human hepatocytes with PXR-specific small interfering RNA reduced the PXR mRNA expression and the extent of CYP3A4 induction by tamoxifen and 4OHT by 50%. Second, in LS174T colon carcinoma cells, which were observed to have significantly lower PXR expression relative to human hepatocytes, neither tamoxifen nor 4OHT induced CYP3A4. Third, N-desmethyltamoxifen, which did not induce CYP3A4 in human hepatocytes, also did not activate PXR in LS174T cells. We then used cell-based reporter assay to evaluate the effects of other receptors such as glucocorticoid receptor GR alpha and estrogen receptor ER alpha on the transcriptional activation of PXR. The cotransfection of GR alpha in LS174T cells augmented PXR activation by tamoxifen and 4OHT. On the other hand, the presence of ER alpha inhibited PXR-mediated basal activation of CYP3A4 promoter, possibly via competing for common cofactors such as steroid receptor coactivator 1 and glucocorticoid receptor interacting protein 1. Collectively, our findings suggest that the CYP3A4 induction by tamoxifen and 4OHT is primarily mediated by PXR but the overall stoichiometry of other nuclear receptors and transcription cofactors also contributes to the extent of the inductive effect.

Sulfasalazine-induced reduction of glutathione levels in breast cancer cells: enhancement of growth-inhibitory activity of Doxorubicin.

BACKGROUND: We previously showed that the anti-inflammatory drug, sulfasalazine (salicylazosulfapyridine, SASP), can arrest proliferation of MCF-7 and MDA-MB-231 mammary cancer cells by inhibiting uptake of cystine via the x(c-) cystine/glutamate antiporter. Here we examined SASP with regard to reduction of cellular glutathione (GSH) levels and drug efficacy-enhancing ability. METHODS: GSH levels were measured spectrophotometrically. Cellular drug retention was determined with 3H-labeled methotrexate, and drug efficacy with a colony formation assay. RESULTS: Incubation of the mammary cancer cells with SASP (0.3-0.5 mM) led to reduction of their GSH content in a time- and concentration-dependent manner. Similar to MK-571, a multidrug resistance-associated protein inhibitor, SASP increased intracellular accumulation of methotrexate. Preincubation of cells with SASP (0.3 mM) significantly enhanced the potency of the anticancer agent doxorubicin (2.5 nM). CONCLUSIONS: SASP-induced reduction of cellular GSH levels can lead to growth arrest of mammary cancer cells and enhancement of anticancer drug efficacy.

Stress and prolactin effects on bone marrow myeloid cells, serum chemokine and serum glucocorticoid levels in mice.

OBJECTIVE: Current evidence supports the conclusion that prolactin (PRL) is not an obligate immunoregulatory hormone and influences the immune system predominantly during stress conditions. In this study, we examined the impact of PRL on the psychogenic stress-induced responses of myeloid cells. METHODS: Seven-week-old PRL+/- (normal) and PRL-/- (deficient) mice were exposed to a predator for 1 h/day on 3 consecutive days. Another group of PRL-deficient mice received either 1 pituitary graft (hyperprolactinemic) or sham surgery at 5 weeks of age, while PRL-normal mice only received sham surgery. Two weeks later, these mice were also subjected to predator exposure. One day after the last predator exposure session, all mice were killed and the bone marrow and blood harvested. RESULTS: Significant differences in the myeloid cells between PRL-normal and PRL-deficient mice only occurred in stressed conditions. The median serum corticosterone levels were consistently higher in PRL-deficient mice. The implantation of a pituitary graft lowered the corticosterone levels to those observed in PRL-normal mice. The absolute number of immature neutrophils as well as the numbers of granulocyte macrophage, monocyte/macrophage and granulocyte colonies were significantly higher in the stressed PRL-deficient mice; however, only the increased number of immature neutrophils was reversed by pituitary grafting. CONCLUSIONS: Our findings support previous observations that PRL influences myeloid cells of the bone marrow most profoundly in stressed conditions. However, the mechanism by which PRL influences bone marrow myeloid cells during stress cannot be explained solely by its effect on serum corticosterone.

Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans.

Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. To test this hypothesis, 2 cross-over outpatient studies were conducted in adults with apo-A IV 1/1 or apo-E 3/3 genotypes. Study 1 included 11 subjects 24 to 37 years of age, taking 15 mg/kg/day chenodeoxycholic acid (CDCA) or no bile acid for 20 days while being fed a controlled diet. Study 2 included 9 adults 25 to 38 years of age, taking 15 mg/kg/day deoxycholic acid (DCA) or no bile acid, following the same experimental design and procedures as study 1. CDCA had no effect on plasma lipid concentrations, whereas DCA decreased (P < 0.05) plasma high-density lipoprotein (HDL)-cholesterol and tended to decrease (P = 0.15) low-density lipoprotein (LDL)-cholesterol. CDCA treatment enriched (P < 0.0001) bile with CDCA and increased cholesterol concentration in micelles, whereas meal-stimulated bile acid concentrations were decreased. DCA treatment enriched (P < 0.0001) bile with DCA and tended to increase intralumenal cholesterol solubilized in micelles (P = 0.06). No changes were found in cholesterol absorption, free cholesterol fractional synthetic rate (FSR), or 3-hydroxy-3 methylglutaryl (HMG) CoA reductase and LDL receptor messenger ribonucleic acid (mRNA) levels after CDCA treatment. DCA supplementation tended to decrease cholesterol absorption and reciprocally increase FSR and HMG CoA reductase and LDL receptor mRNA levels. Results of these 2 studies suggest that the solubilization of cholesterol in the intestinal micelles is not a rate-limiting step for its absorption.

Effective dose of dual-energy X-ray absorptiometry scans in children as a function of age.

Effective dose, a parameter utilized to assess biological risk related to radiation exposure, may be used to evaluate risk associated with dual-energy X-ray absorptiometry (DXA). We estimated the effective dose from DXA (Hologic QDR 4500A) scans of the lumbar spine (fast array mode), total body, hip (fast array mode), and forearm for children ages 1, 5, 10, and 15 yr and for adults. Entrance dose incorporating backscatter was determined for each scan type. Depth-dose curves were derived using Plexiglas slabs simulating tissue attenuation. Organ depth was estimated using pediatric phantom models. For all scan types, the effective dose decreased as age increased. The effective dose values for a 1-yr-old and an adult, respectively, were 4.7 microSv and 2.2 microSv for a lumbar spine scan performed in fast array mode, 3.4/3.5 microSv and 1.8/2.1 microSv (male/female) for a total body scan, and 0.14 microSv and 0.03 microSv for a forearm scan. There were marked sex differences in the effective dose associated with hip scans (fast array mode) ranging from 15.2 microSv for a 1-yr-old male to 4.6 microSv for an adult female. A comprehensive uncertainty analysis indicated that the effective dose values were reliable within a factor of 3. With the exception of the hip scans in 1- and 5-yr-olds, the effective doses were below the negligible individual dose limit of 10 microSv/yr.

Nitric oxide mediates increased P-glycoprotein activity in interferon-{gamma}-stimulated human intestinal cells.

Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN-gamma and nitric oxide (NO) levels. Using the in vitro Caco-2 cell culture model, we investigated whether these pathological mediators associated with the etiology of IBD affect functional activity of intestinal efflux systems. IFN-gamma reduced cellular uptake of cyclosporin A (CysA) but not methotrexate (MTX) in a time- and concentration-dependent manner. Simultaneously, P-gp expression increased by approximately twofold. Coincubation with the inducible NO synthase inhibitor l-N(6)-(1-iminoethyl)lysine (l-NIL) dramatically reduced production of intracellular NO in response to IFN-gamma stimulus. The presence of l-NIL also abrogated the cytokine-mediated increase in P-gp expression and function suggesting that NO is required for IFN-gamma-mediated activation of this efflux system. Exposure of Caco-2 cells to the chemical NO donor S-nitroso-N-acetylpenicillamine (SNAP) produced a concentration-dependent decrease in intracellular CysA accumulation that was paralleled by an increase in P-gp expression. Both IFN-gamma and SNAP enhanced DNA binding of NF-kappaB, whereas inclusion of l-NIL dramatically decreased this cytokine-induced effect on NF-kappaB binding. These results suggest that NO mediates IFN-gamma-induced increase in expression and function of intestinal P-gp in the human Caco-2 cell culture model by altering DNA binding of NF-kappaB, which may enhance transcription of the ABCB1 gene encoding for this efflux system.

Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital.

The antiretroviral agent efavirenz enhances the systemic clearance of coadministered drugs that are cytochrome P450 (CYP) 3A4 substrates. The mechanism of the apparent increase in CYP3A4 activity by efavirenz and the magnitude of change relative to other known inducers are not known. The authors tested the hypothesis that increased enzymatic activity by efavirenz entails CYP3A4 induction and activation of the human pregnane X receptor (hPXR), a key transcriptional regulator of CYP3A4. Employing primary cultures of human hepatocytes, they compared the CYP3A4 inductive effects of efavirenz (1-10 microM) to rifampin (10 microM) and phenobarbital (2 mM). A cell-based reporter assay was employed to assess hPXR activation. The authors observed that efavirenz caused a concentration-dependent CYP3A4 induction and hPXR activation. Based on the CYP3A4 activity assay, the average magnitude of induction by efavirenz (5-10 microM) was approximately 3- to 4-fold. In comparison, phenobarbital (2 mM) and rifampin (10 microM) caused a 5- and 6-fold induction, respectively.

Differences in the induction of cytochrome P450 3A4 by taxane anticancer drugs, docetaxel and paclitaxel, assessed employing primary human hepatocytes.

PURPOSE: The induction of cytochrome P450 (CYP) 3A4 by drugs and other xenobiotics is a common cause of serious drug interactions. The aim of this study was to comparatively examine the effects of paclitaxel and docetaxel, two structurally related taxane anticancer agents, on the activity and expression of hepatic CYP3A4. METHODS: Employing primary cultures of human hepatocytes from multiple donors, we investigated the differences in the magnitude of CYP3A4 induction and relative accumulation of paclitaxel and docetaxel. The CYP3A4 activity of intact hepatocytes was measured as the rate of testosterone 6beta-hydroxylation. The CYP3A4-specific immunoreactive protein and mRNA levels were measured employing Western blot and Northern blot analysis, respectively. Furthermore, employing cell-based reporter gene assay in CV-1 cells, we evaluated the capacity of paclitaxel and docetaxel to activate human pregnane X receptor (hPXR), an orphan nuclear receptor that plays a key role in the transcriptional regulation of CYP3A4. RESULTS: In concurrence with previous reports, we observed that paclitaxel potently induced CYP3A4 activity and expression in hepatocytes treated for 48-96 h. However, docetaxel did not increase the activity or the CYP3A4 immunoreactive protein levels for treatment periods up to 96 h. A marginal increase in the CYP3A4 mRNA levels was observed in cells treated with higher levels (5 and 10 microM) of docetaxel. Furthermore, while paclitaxel effectively activated hPXR (the half-maximal effective concentration, EC50, being about 5.2 microM), docetaxel weakly activated hPXR, and moreover the activation occurred only at high concentrations relative to paclitaxel. A comparison of the cellular concentrations of paclitaxel and docetaxel, in the cell culture models employed for evaluating CYP3A4 induction and hPXR activation, revealed that the intracellular paclitaxel levels were three-fold higher than that of docetaxel. Thus, it appears that both pharmacokinetic (drug concentration) and pharmacodynamic differences (hPXR activation) may account for the observed differences in CYP3A induction by paclitaxel and docetaxel. CONCLUSION: Our studies suggest that docetaxel has markedly reduced propensity to cause drug interactions that may entail hepatic CYP3A4 induction.