Drug metabolism and liver disease: a drug-gene-environment interaction.

Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.

The relationship between pulmonary emphysema and kidney function in smokers.

BACKGROUND: It has been reported that the prevalence of kidney dysfunction may be increased in patients exposed to tobacco with airflow obstruction. We hypothesized that kidney dysfunction would associate with emphysema rather than with airflow obstruction measured by the FEV1. METHODS: Five hundred eight current and former smokers completed a chest CT scan, pulmonary function tests, medical questionnaires, and measurement of serum creatinine. Glomerular filtration rates (eGFRs) were estimated using the method of the Chronic Kidney Disease Epidemiology Collaboration. Quantitative determinants of emphysema and airway dimension were measured from multidetector chest CT scans. RESULTS: The mean age was 66 ± 7 years, and mean eGFR was 101 ± 22 mL/min/1.73 m². Univariate and multivariate analysis showed a significant association between radiographically measured emphysema and eGFR: Participants with 10% more emphysema had an eGFR that was lower by 4.4 mL/min/1.73 m² (P = .01), independent of airflow obstruction (FEV1), age, sex, race, height, BMI, diabetes mellitus, hypertension, coronary artery disease, patient-reported dyspnea, pack-years of smoking, and current smoking. There was no association between eGFR and either FEV1 or quantitative CT scan measures of airway dimension. CONCLUSIONS: More severe emphysema, rather than airflow obstruction, is associated with kidney dysfunction in tobacco smokers, independent of common risk factors for kidney disease. This finding adds to recent observations of associations between emphysema and comorbidities of COPD, including osteoporosis and lung cancer, which are independent of the traditional measure of reduced FEV1. The mechanisms and clinical implications of kidney dysfunction in patients with emphysema need further investigation.

Radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort.

RATIONALE: Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied. OBJECTIVES: We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers. METHODS: One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed. MEASUREMENTS AND MAIN RESULTS: No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24-5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use. CONCLUSIONS: Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.

A UPLC-MS/MS assay of the "Pittsburgh cocktail": six CYP probe-drug/metabolites from human plasma and urine using stable isotope dilution.

The efficiency of drug metabolism by a single enzyme can be measured as the fractional metabolic clearance which can be used as a measure of whole body activity for that enzyme. Measurement of activity of multiple enzymes simultaneously is feasible using a cocktail approach, however, analytical approach using different assays for drug probes can be cumbersome. A quantitative ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) based method for the rapid measurement of six cytochrome P450 (CYP) probe drugs and their relevant metabolites is described. The six specific probe substrates/metabolites are caffeine/paraxanthine (CYP1A2), flurbiprofen/4'-hydroxyflurbiprofen (CYP2C9), mephenytoin/4'-hydroxymephenytoin (CYP2C19), debrisoquine/4-hydroxydebrisoquine (CYP2D6), chlorzoxazone/6'-hydroxychlorzoxazone (CYP2E1) and dapsone/N-monoacetyldapsone (NAT2). These probes were quantified by stable isotope dilution from plasma and urine. The present workflow provides a robust, fast and sensitive assay for the "Pittsburgh cocktail", and has been successfully applied to a clinical phenotyping study of liver disease. A representative group of 17 controls and patients with chronic liver disease were administered orally caffeine (100 mg), chlorzoxazone (250 mg), debrisoquine (10 mg), mephenytoin (100 mg), flurbiprofen (50 mg) and dapsone (100 mg). Urine (0 through 8 h) and plasma (4 and 8 h) samples were analyzed for drug/metabolite amounts by stable isotope dilution UPLC-MS/MS. The phenotypic activity of drug metabolizing enzymes was investigated with 17 patient samples. Selected reaction monitoring (SRM) was optimized for each drug and metabolite. In the method developed, analytes were resolved by reversed-phase by development of a gradient using a water/methanol solvent system. SRM of each analyte was performed in duplicate on a triple quadrupole mass spectrometer utilizing an 8 min analytical method each, one with the source operating in the positive mode and one in the negative mode, using the same solvent system. This method enabled quantification of each drug (caffeine, chlorzoxazone, debrisoquine, mephenytoin, flurbiprofen, and dapsone) and its resulting primary metabolite in urine or plasma in patient samples. The method developed and the data herein demonstrate a robust quantitative assay to examine changes in CYP enzymes both independently or as part of a cocktail. The clinical use of a combination of probe drugs with UPLC-MS/MS is a highly efficient tool for the assessment of CYP enzyme activity in liver disease.

Significance of increased serum GGTP levels in HCC patients.

A large dataset of patients with biopsy-proven and unresectable HCC who were prospectively followed from diagnosis till death, was examined for the prognostic significance of serum GGTP levels. Their survival-ordered baseline clinical parameter data was examined. Two cohorts of patients with both low AFP and bilirubin levels were identified, who had serum GGTP levels with an increasing trend with increasing AFP levels. The survival of these patients also decreased as their GGTP levels trended up, as did their tumor masses. By contrast, in patients with elevated serum AFP levels, the GGTP trends were less informative, although patients with the highest AFP levels had a worse prognosis if their GGTP levels were simultaneously elevated. The results suggest that following trends in serum GGTP levels, in the context of specific ranges of AFP and bilirubin levels, might be useful in diagnosis of small HCCs.

Low alpha-fetoprotein hepatocellular carcinoma.

BACKGROUND AND AIM: A large proportion of hepatocellular carcinoma (HCC) patients do not secrete elevated levels of the tumor marker alpha-fetoprotein (AFP). There is little published guide to prognostic features of this patient subset. METHODS: We interrogated a large HCC database in which all patients had been followed until death, to examine which features might be prognostically useful. RESULTS: We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum gamma glutamyl transpeptidase (GGTP) levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels < 110 U/100 mL and small tumors had longest survival > 795 days. Patients with GGTP > or = 110 U/mL and large tumors with the presence of portal vein thrombosis had the shortest survival range of 300-560 days. CONCLUSIONS: Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.

HCC in young adults.

A large cohort of unresectable and untransplantable biopsy-proven HCC patients was rank-ordered for survival. Non-random clustering by age was noted, with 3 sub-cohorts of younger patients with survival in the range of 90-360 days. One sub-cohort had a predominance of females. Tumor numbers were well monitored by serum AFP, but tumor mass was better monitored by serum GGTP. In contrast to the older patients, the probability of hepatitis appeared to have a major impact on their survival and these patients tended to have larger numbers of smaller tumors, consistent with the idea of a hepatitis-mediated carcinogenic field defect.

Network-based analysis of survival for unresectable hepatocellular carcinoma.

Primary hepatocellular cancer (HCC) classification systems are based on histopathology and radiology, yet clinical intuition and experience suggest that natural history and disease progression have distinctive clinical features, consistent with a cluster of homogeneous entities within a heterogeneous cohort. We built a rigorous, sequenced, graph-based strategy of network phenotyping analysis (NPA) to combine data smoothing to minimize stochasticity, multivariate analysis to identify ambiguity and prioritize key variables, and k-partite graphs to visualize coherence. In 890 unresectable HCC patients, we selected 13 baseline clinical variables. After rank ordering by survival, we found data structure that exhibited coherence between variables, implying heterogeneity in which survival varied depending on the associated variable profile. The NPA data compression identified five distinctive clinical phenotypes, based only on gender, age, and levels of serum bilirubin, serum alpha-fetoprotein (AFP), and serum gamma glutamyl transpeptidase (GGTP). The phenotypic profiles for gender and age were substantially different. Young, male patients had a low survival, while elderly women had a long survival. Novel clusters included young men, with high AFP levels for their level of bilirubin, as well as women of all ages, with high GGTP values for their level of AFP. The identification of phenotypic groups of HCC may be of value in studies designed to understand their underlying pathophysiology. We conclude that NPA offers a new useful tool in the reclassification of HCC.

HCC in older patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous disease, with many poorly-defined prognostic patient subsets. Identification of discrete subsets will aid rational patient and treatment selection. METHODS: A database with 778 biopsy-proven, unresectable and untransplantable HCC patients who were followed from diagnosis till death was interrogated. Using a moving average algorithm, patients were ordered by survival and then survival cohorts were analyzed according to standard liver function and CT characteristic parameters. RESULTS: We found characteristic age clustering groupings by survival. In the older age patients, two survival sub-groups were identified, with 45-80 days in one and 330-1,250 days survival in the other group. The longer surviving group had the lowest serum bilirubin and AFP levels and the lowest tumor mass. Remarkably, the trends for both AFP and bilirubin were similar, suggesting that they were not independent variables. This idea was supported by the similar correlation of typical AFP with GGTP, ALKP and SGOT levels. CONCLUSIONS: A large HCC cohort showed significant age clustering characteristics for survival, especially in older patients. AFP, bilirubin and age were found to be inter-related factors for HCC severity and survival.

Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study.

BACKGROUND: Intrahepatic arterial yttrium 90 ((90)Y) microspheres have been proposed as a less toxic, less invasive therapeutic option to transhepatic arterial chemoembolization (TACE) for patients with surgically unresectable hepatocellular carcinoma (HCC). TACE has demonstrated the ability to prolong survival. However, long-term survival remains uncertain. METHODS: In a 2-cohort experience in the treatment of North American patients who had advanced, unresectable, biopsy-proven HCC, 691 patients received repetitive, cisplatin-based chemoembolization; and a separate cohort of 99 patients who had similar treatment criteria received a planned, single dose of (90)Y. Over the study period, an additional 142 patients were followed without treatment (total, 932 patients). RESULTS: Overall survival was slightly better in the (90)Y group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a small but significant bias toward milder disease in the (90)Y group. By using stratification into a 3-tier model with patients dichotomized according to bilirubin levels <1.5 mg/dL, the absence of portal vein thrombosis (PVT), and low alpha-fetoprotein plasma levels (<25 U/dL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival. In addition, patients who had PVT or high alpha-fetoprotein levels also had similar survival in both treatment groups. CONCLUSIONS: Given the current evidence of therapeutic equivalence in survival, (90)Y and TACE appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC.

The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD. METHODOLOGY/PRINCIPAL FINDINGS: Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status. CONCLUSIONS/SIGNIFICANCE: Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study.

OBJECTIVES: 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point. RESULTS: We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival. CONCLUSION: The data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.

Feasibility of adolescents to conduct community-based participatory research on obesity and diabetes in rural Appalachia.

Community-Based Participatory Research (CBPR) has been advocated to translate advances in health care sciences to the community. We describe a novel approach applied to obesity management and diabetes prevention. This takes advantage of a network of science clubs organized by the Health Sciences and Technology Academy (HSTA) for extracurricular activity of disadvantaged high school students in rural Appalachia. Physician scientists and educators provided an intensive summer course on CBPR, ethics, and study design on obesity management and diabetes prevention. Ethical certification for CBPR investigation was obtained for 210 students and 18 mentors for a study on the prevalence of obesity and Type II diabetes within their community. Over a 6-month period, 989 had a collection of complete analyzable data, of which 103 had diabetes. The proportion with obesity (BMI > or = 30) was over 50%. The frequency of diabetes was related to increasing BMI. When BMI > or = 40, the frequency approached 50%, and exhibited a clear familial distribution. We conclude that trained adolescents can effectively conduct CBPR, and obesity and diabetes are more prevalent than previously reported in this community. This experience provides encouragement to conduct future studies to infl uence weight management from high-risk populations in this medically disadvantaged community.

Team building: electronic management-clinical translational research (eM-CTR) systems.

Classical drug exposure: response studies in clinical pharmacology represent the quintessential prototype for Bench to Bedside-Clinical Translational Research. A fundamental premise of this approach is for a multidisciplinary team of researchers to design and execute complex, in-depth mechanistic studies conducted in relatively small groups of subjects. The infrastructure support for this genre of clinical research is not well-handled by scaling down of infrastructure used for large Phase III clinical trials. We describe a novel, integrated strategy, whose focus is to support and manage a study using an Information Hub, Communication Hub, and Data Hub design. This design is illustrated by an application to a series of varied projects sponsored by Special Clinical Centers of Research in chronic obstructive pulmonary disease at the University of Pittsburgh. In contrast to classical informatics support, it is readily scalable to large studies. Our experience suggests the culture consequences of research group self-empowerment is not only economically efficient but transformative to the research process.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a case cohort study.

BACKGROUND AND AIMS: A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. METHODS: Survival was the end-point for all analyses. RESULTS: We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient subgroups based on poor liver function and aggressive tumor characteristics. In subgroup analysis based on these subsets, there was clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant, independent but modest risk factors. The results of this large dataset show that amongst nonsurgical HCC patients, there are clear subsets with longer survival than other subsets. CONCLUSIONS: This data also supports the concept of heterogeneity of HCC.

Gender-based outcomes differences in unresectable hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC is notably more prevalent in males worldwide, with reported male:female ratios ranging from 2:1 to 8:1. The reasons for sex differences in the incidence of HCC are unclear. Furthermore, differences in rates of disease progression and longevity are not well studied and few series have compared the clinicopathologic characteristics of patients and their impact on survival with specific reference to gender in a large sample set. METHODS: The present study is a large single-institution study of 1138 HCC cases referred to a single individual carried out over a period of 17 years. The primary endpoint measure was over-all survival measured in months, which was defined as the time between the date of diagnosis and date of death. Differences in median survival for each subgroup analysis in survival rates were compared by log rank test. RESULTS: There are differences in both the distribution of evidence of disease progression at the time of diagnosis and the time for survival following diagnosis in patients with HCC between the two genders. Females had a longer survival than males in subsets matched for residual liver function and tumor extension, suggesting that the natural history of HCC is different between men and women. CONCLUSION: The present study provides evidence that female gender provides a distinct survival advantage over males in unresectable HCC presenting with similar tumor characteristics, liver function, and coexisting liver disease.

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by varying degrees of airflow limitation and diffusion impairment. There is increasing evidence to suggest that COPD is also characterized by systemic inflammation. The primary goal of this study was to identify soluble proteins in plasma that associate with the severity of airflow limitation in a COPD cohort with stable disease. A secondary goal was to assess whether unique markers associate with diffusion impairment, based on diffusion capacity of carbon monoxide (DLCO), independent of the forced expiratory volume in 1 second (FEV1). METHODS: A cross sectional study of 73 COPD subjects was performed in order to examine the association of 25 different plasma proteins with the severity of lung function impairment, as defined by the baseline measurements of the % predicted FEV1 and the % predicted DLCO. Plasma protein concentrations were assayed using multiplexed immunobead-based cytokine profiling. Associations between lung function and protein concentrations were adjusted for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use. RESULTS: Plasma concentrations of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1), CCL4/macrophage inflammatory protein-1 beta (CCL4/MIP-1 beta), CCL11/eotaxin, and interleukin-13 (IL-13) were inversely associated with the % FEV1. Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-gamma (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL-13 showed inverse relationships with the % DLCO. CONCLUSION: Systemic inflammation in a COPD cohort is characterized by cytokines implicated in inflammatory cell recruitment and airway remodeling. Plasma concentrations of IL-13 and chemoattractants for monocytes, T lymphocytes, and eosinophils show associations with increasing severity of disease. Soluble Fas, G-CSF and CXCL9/Mig may be unique markers that associate with disease characterized by disproportionate abnormalities in DLCO independent of the FEV1.

Clinical outcomes of intravenous immune globulin in severe clostridium difficile-associated diarrhea.

OBJECTIVES: Our objective was to determine if use of intravenous immune globulin (IVIG) decreases the incidence of mortality, colectomies, and length of stay in the hospital in patients presenting with severe Clostridium difficile-associated diarrhea (CDAD). METHODS: A retrospective analysis was undertaken of 79 patients who had a positive C. difficile toxin titer and severe disease admitted to the University of Pittsburgh Medical Center Presbyterian between July 2001 and July 2003. Standard therapy for severe CDAD including intravenous metronidazole, oral vancomycin, or vancomycin enema was administered to all patients. Eighteen patients also received IVIG treatment (200-300 mg/kg); these were pair matched by propensity scoring with 18 patients who had the most similar characteristics and severity of CDAD from the available pool of 61 subjects who did not receive IVIG treatment. RESULTS: No significant difference was observed in the baseline characteristics between the two groups. There were no statistical differences in clinical outcomes as measured by all cause mortality, colectomies, and length of stay. CONCLUSIONS: These data demonstrate that the use of IVIG in severe CDAD remains unsubstantiated. This study, although limited by a small sample size, does not support the use of IVIG at this dose for severe CDAD outside of a controlled trial.

Monocyte fructose 1,6-bisphosphatase and cytidine deaminase enzyme activities: potential pharmacodynamic measures of calcitriol effects in cancer patients.

PURPOSE: To determine, in peripheral blood monocytes (PBM), whether the enzymatic activities of fructose 1,6-bisphosphatase (FBPase), cytidine deaminase (CDDase) and 24-hydroxylase (CYP24), enzymes regulated by calcitriol are useful pharmacodynamic (PD) measures of calcitriol effects in cancer patients. METHODS: Cancer patients enrolled in a phase I clinical trial of calcitriol and carboplatin were studied. Baseline and calcitriol-induced changes in FBPase, CDDase and CYP24 activities were measured in PBM collected before, 6, 24, and 48 h after administration of calcitriol, prior to carboplatin, in doses ranging from 4 to 11 mug daily for 3 consecutive days (QDx3). Normal FBPase, CYP24 and CDDase activities were measured in PBM from untreated healthy volunteers. RESULTS: Baseline activities in PBM from cancer patients and healthy volunteers were (median and range): 1.0 (0.0-43.5) and 4.4 (3.1- 8.2) nmol/min/mg protein for FBPase (P = 0.002); 2.5 (0.9-9.3) and 0.8 (0.4-2.0) fmol/h/10(6) cells for CYP24 (P = 0.016), and 5.6 (2.5-22.3) and 6.6 (1.1-47.4) nmol/min/mg protein for CDDase (P > 0.05), respectively. All calcitriol doses achieved peak serum calcitriol levels > x3 the physiological levels, increased cancer patient PBM FBPase activity to normal levels and decreased CDDase activity to undetectable levels within 48 h, with no significant change in CYP24 activity. These enzyme activity changes were not associated with hypercalcemia. CONCLUSIONS: Calcitriol treatment-induced increase in FBPase and decrease in CDDase activities in cancer patient PBM are potential early and sensitive non-hypercalcemia PD measures of calcitriol effects.