Journey towards resiliency: A systematic review and meta-synthesis of cancer patients' experiences.

PURPOSE: This systematic review and meta-synthesis seeks to explore cancer patients' journey towards resiliency. The secondary aim of this review is to identify unique resilience protective factors among cancer patients. METHODS: A thorough search was conducted in eight electronic databases and the grey literature for published or unpublished qualitative and mixed methods studies. Studies that explored resilience among cancer patients were included. The studies were appraised using the Critical Appraisal Skill Programme Checklist. The overall certainty of evidence was further evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation's Confidence in Evidence from Reviews of Qualitative Research. Themes identified were synthesized using Sandelowski and Barroso's meta-synthesis method. RESULTS: A total of 34 studies comprising 987 cancer patients were included in this review. Three themes and nine subthemes were generated from the meta-synthesis. The themes were: (1) Confronting the cancer diagnosis, (2) personal adaptations to cancer, and (3) drawing strength from others. The findings highlighted how individuals overcame cancer adversities through resilience, which is influenced by various factors, including life experiences, social-cultural stigmas, spirituality, social support networks, coping strategies, motivation, acceptance of illness, positive mindset, and engagement with healthcare facilities. CONCLUSIONS: This review highlights the role of resilience in a cancer patient's journey. It emphasizes on the importance of building resilience in both cancer patients and survivors to effectively overcome the challenges of their cancer diagnosis. These insights are essential for developing interventions that promote resilience and improve existing psychosocial oncology services. Future research should focus on longitudinal studies to better understand how resilience evolves and pinpoint factors that can further influence one's resilience.

Evaluating the online Resilience Skills Enhancement programme among undergraduate students: A double-blind parallel randomized controlled trial.

Resilience training has beneficial effects on the ability of undergraduate students to withstand adversity and stress. However, there are inconsistencies in the content and delivery approaches for resilience training. Given the increasing shifts towards computer-assisted instruction, there is a need to develop and evaluate innovative approaches for resilience training. This study aimed to examine the efficacy of two versions of the Resilience Skills Enhancement (RISE) programme. A randomized controlled trial was used to evaluate the effects of blended learning (BL) and a self-guided RISE programme on the resilience, social support, and learning outcomes of undergraduate students. One hundred and fourteen students were recruited and randomly allocated to receive either BL or the self-guided RISE programme. The within-group analyses indicated significant improvements in resilience scores for the BL (F = 37.74, p < 0.001) and self-guided groups (F = 10.16, p < 0.001) with moderate (d = 0.62, 95% CI: 0.25, 1.00) to large effect sizes (d = 1.11, 95% CI: 0.71, 1.50) respectively. There were also significant differences across the three time points for social support scores for the BL (F = 4.50, p < 0.05) and self-guided groups (F = 4.59, p < 0.05). Students in the BL group had considerable improvements in self-efficacy of learning and performance (F = 5.42, p < 0.01) and meta-cognitive self-regulation scores (F = 5.91, p < 0.01). In the between-group analyses, both BL and self-guided RISE were comparable for resilience, social support, and learning scores (p > 0.05). The study provided preliminary evidence that both modes, BL and self-guided RISE programme lead to positive effects on the resilience, social support, and learning scores of students.

Resilience for Undergraduate Students: Development and Evaluation of a Theory-Driven, Evidence-Based and Learner Centered Digital Resilience Skills Enhancement (RISE) Program.

Protective factors that build students' resilience are known. A six-week digital resilience training program was developed on the basis of theory, evidence, and contextual information. The feasibility study sought to evaluate the acceptability, appropriateness, demand, implementation, and limited efficacy of a digital resilience skills enhancement program for undergraduate students. A single group, pre-test, post-test, concurrent mixed methods design among 10 undergraduate students was conducted in one university in Singapore. The content analysis concluded that students accepted and perceived the digital resilience skills enhancement program as appropriate. Students also proposed several improvements, such as the initiation of the program and revisions to the content. The Wilcoxon signed-rank test found significant improvements in resilience (p = 0.02) and meta-cognitive self-regulation (p = 0.01) scores with medium (d = 0.79, 95% CI: -0.15 to 1.74) and very large effect sizes (d = 1.31, 95% CI: 0.30-2.33), respectively. Students found the digital resilience program appropriate and were able to apply their newly acquired skills to promote their resilience and learning. Although, several improvements are proposed to enhance the rigor of the digital resilience program, the findings of this study suggests that digital resilience programs are important for students' well-being.

Spotlight on noncognitive skills: Views from nursing students and educators.

BACKGROUND: Noncognitive skills have a considerable role in influencing nursing students' performance in clinical and educational settings. Understanding how nursing students and educators perceive noncognitive skills is important given the broad classifications of noncognitive competencies. OBJECTIVE: This study sought to examine nursing students' and educators' perception of noncognitive skills. DESIGN: This study adopted a descriptive qualitative approach. SETTING: This study was conducted virtually via Zoom in one university in Singapore. PARTICIPANTS: Purposive sampling through a maximum variation technique was used to select 35 nursing students and 12 educators. METHODS: Semistructured interviews were conducted through eight virtual face-to-face focus group discussions. Interviews were audio- and videorecorded and transcribed verbatim. Data were analysed through thematic analysis. RESULTS: The participants stated that individual and interpersonal skills contribute to one's noncognitive skills. Two themes emerged from the participants' narratives: (1) the ability to manage oneself and (2) social interactions with others. The first theme describes the various individual characteristics such as growth mindset, adaptability, resilience, and emotional regulation. The second theme describes the importance of empathy and meaningful relationships as types of non-cognitive skills. CONCLUSIONS: The findings of this study provide the basis for the development of noncognitive assessment tools by educators. In addition, they pave the foundation for the curation of future programs that promote the noncognitive skills of nursing students. Hospital-based educators may use these findings to curate suitable programs for improving the noncognitive abilities of nurses.

Novel CD8+ T-Cell Subsets Demonstrating Plasticity in Patients with Inflammatory Bowel Disease.

BACKGROUND: Distinct CD8+ T-cell subsets such as interleukin-17-expressing Tc17 and Foxp3-expressing Tcreg are functionally similar to CD4+ T cells. Though CD4+ T cells are dysregulated in patients with inflammatory bowel disease (IBD), CD8+ T cells are not well investigated. Vitamin D is an environmental factor which influences T-cell subsets. We assessed the prevalence of CD8+ T-cell subsets among peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC) of patients with Crohn's disease, patients with ulcerative colitis, and healthy controls. We then tested the effect of 1α,25-dihydroxyvitamin D3 on CD8+ T-cell subsets. METHODS: A total of 73 patients with Crohn's disease, 49 patients with ulcerative colitis, and 47 healthy controls were studied. LPMC or PBMC were isolated and flow cytometry was performed. CD3+ T cells, isolated from PBMC, were cultured with or without 1α,25-dihydroxyvitamin D3, before flow cytometry. RESULTS: In LPMC, the prevalence of Tcreg was higher in patients with IBD (P < 0.05), whereas Tc17 were higher in patients with ulcerative colitis compared with patients with Crohn's disease and healthy controls (P < 0.05). In PBMC, both Tcreg and Tc17 were higher in patients with IBD (P < 0.01). Double-expressing interferon-γ+ interleukin-17+ and Foxp3+ interleukin-17+ CD8+ T cells were also identified indicating possible CD8+ plasticity. 1α,25-dihydroxyvitamin D3 decreased interferon-γ-expressing Tc1 (P < 0.05), but had no effect on Tc17 or Tcreg. CONCLUSIONS: The prevalence of novel CD8+ T-cell subsets is altered in patients with IBD. Double-expressing cells indicate plasticity and were identified in patients with IBD. Vitamin D may have a limited effect on CD8+ T cells by decreasing interferon-γ expression.

Th17 plasticity and its changes associated with inflammatory bowel disease.

CD4 T helper (Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently, the paradigm held that naïve T cells differentiated into distinct subsets under the guidance of environmental cues (e.g., cytokines) and that once polarized, these cells were committed to a particular functional state. However, the existence of transdifferentiated T cell populations, which express signature transcription factors and cytokines associated with more than one Th subset, challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases (IBD) and the machinery that underlies this process is far from fully understood. Interleukin (IL)-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD, human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells, which, can also secrete interferon-γ, the signature cytokine for Th1 cells or, can co-express the anti-inflammatory transcription factor forkhead box p3, a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity, mechanisms, which govern it, and highlight the potential to therapeutically target this process in human IBD.

Outcome of severely injured trauma patients at a designated trauma centre in the Hong Kong Special Administrative Region.

BACKGROUND: The Hong Kong Special Administrative Region (HKSAR) of the People's Republic of China (PRC) has seen significant changes in its trauma service over the last ten years including the implementation of a regional trauma system. The author's institution is one of the five trauma centres designated in 2003. This article reports our initial clinical experience. METHODS: A prospective single-centre trauma registry from January 2004 to December 2008 was reviewed. The primary clinical outcome measure was hospital mortality. The Trauma and Injury Severity Score (TRISS) methodology was used for bench-marking with the North America Major Trauma Outcome Study (MTOS) database. RESULTS: There were 1451 patients. The majority (83.9%) suffered from blunt injury. The overall mortality rate was 7.8%. Severe injury, defined as the Injury Severity Score > 15, occurred in 22.5% of patients, and was associated with a mortality rate of 31.6%. A trend of progressive improvement was noted. The M-statistic was 0.99, indicating comparable case-mix with the MTOS. The Z- and W-statistics of each individual year revealed fewer, but not significantly so, number of survivors than expected. CONCLUSIONS: Trauma centre designation was feasible in the HKSAR and was associated with a gradual improvement in patient care. Trauma system implementation may be considered in regions equipped with the necessary socio-economic and organizational set-up.

Outcome of severely injured trauma patients at a designated trauma centre in the Hong Kong Special Administrative Region / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The Hong Kong Special Administrative Region (HKSAR) of the People's Republic of China (PRC) has seen significant changes in its trauma service over the last ten years including the implementation of a regional trauma system. The author's institution is one of the five trauma centres designated in 2003. This article reports our initial clinical experience.</p><p><b>METHODS</b>A prospective single-centre trauma registry from January 2004 to December 2008 was reviewed. The primary clinical outcome measure was hospital mortality. The Trauma and Injury Severity Score (TRISS) methodology was used for bench-marking with the North America Major Trauma Outcome Study (MTOS) database.</p><p><b>RESULTS</b>There were 1451 patients. The majority (83.9%) suffered from blunt injury. The overall mortality rate was 7.8%. Severe injury, defined as the Injury Severity Score > 15, occurred in 22.5% of patients, and was associated with a mortality rate of 31.6%. A trend of progressive improvement was noted. The M-statistic was 0.99, indicating comparable case-mix with the MTOS. The Z- and W-statistics of each individual year revealed fewer, but not significantly so, number of survivors than expected.</p><p><b>CONCLUSIONS</b>Trauma centre designation was feasible in the HKSAR and was associated with a gradual improvement in patient care. Trauma system implementation may be considered in regions equipped with the necessary socio-economic and organizational set-up.</p>

Kinetic analysis of saturable hepatic uptake of digoxin and its inhibition by rifampicin.

Although the organic anion transporter Oatp2 plays a critical role in determining the hepatic clearance of some drugs, little quantitative information exists about its functional characteristics in relation to inhibition of sinusoidal drug uptake. We investigated the uptake kinetics of the Oatp2 substrate digoxin in the isolated perfused rat liver. In the single-pass perfused liver three consecutive digoxin doses of 15, 30 and 45 micorg were administered in the presence or absence of rifampicin (100 micorM), an inhibitor of Oatp2. Digoxin was determined in the outflow samples by HPLC and all data were analyzed by simultaneous nonlinear regression assuming a Michaelis-Menten uptake mechanism. Hepatocellular uptake of digoxin was concentration-dependent with a Michaelis constant (K(M)) of 577.8 ng/ml. Rifampicin significantly reduced uptake (K(M) increased 2.5-fold) without affecting other parameters.

Physiologically based synthetic models of hepatic disposition.

Current physiologically based pharmacokinetic (PBPK) models are inductive. We present an additional, different approach that is based on the synthetic rather than the inductive approach to modeling and simulation. It relies on object-oriented programming. A model of the referent system in its experimental context is synthesized by assembling objects that represent components such as molecules, cells, aspects of tissue architecture, catheters, etc. The single pass perfused rat liver has been well described in evaluating hepatic drug pharmacokinetics (PK) and is the system on which we focus. In silico experiments begin with administration of objects representing actual compounds. Data are collected in a manner analogous to that in the referent PK experiments. The synthetic modeling method allows for recognition and representation of discrete event and discrete time processes, as well as heterogeneity in organization, function, and spatial effects. An application is developed for sucrose and antipyrine, administered separately and together. PBPK modeling has made extensive progress in characterizing abstracted PK properties but this has also been its limitation. Now, other important questions and possible extensions emerge. How are these PK properties and the observed behaviors generated? The inherent heuristic limitations of traditional models have hindered getting meaningful, detailed answers to such questions. Synthetic models of the type described here are specifically intended to help answer such questions. Analogous to wet-lab experimental models, they retain their applicability even when broken apart into sub-components. Having and applying this new class of models along with traditional PK modeling methods is expected to increase the productivity of pharmaceutical research at all levels that make use of modeling and simulation.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation.

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

Symptom distress as rated by advanced cancer patients, caregivers and physicians in the last week of life.

OBJECTIVES: To study the symptom distress as rated by patients with advanced cancer during their last week of life, and to compare patients' ratings with those perceived by caregivers and physicians. METHOD: This was a prospective study on all patients admitted to the Hospice Unit of the Caritas Medical Centre with an estimated life expectancy of two weeks or less from May 2002 to September 2002. A questionnaire with a list of 13 symptoms, including pain, dyspnoea, nausea, vomiting, dry mouth, cough, fatigue, cachexia, anorexia, constipation, diarrhoea, insomnia and haemoptysis, was administered to assess the distress. Distress was rated by a verbal rating scale consisting of five grades (grade 0 to grade 4). Patients, caregivers and physicians completed the questionnaire weekly until the patient died. Only the questionnaires completed in the last week of life were included for analysis. RESULTS: Of 82 patients who were recruited in the study, 30 patients were able to complete the questionnaire within the last week of life. Their median age was 69 years and the gender ratio was 1:1. Lung cancer was the most common primary tumour. Fatigue, cachexia and anorexia caused distress of all grades in nearly all 30 patients and caused significant distress of grade 3 and above in two-thirds of patients. Neither the caregivers nor the physicians gave congruent distress scores for these three symptoms (kappa<0.4). Caregivers' ratings agreed well with those of patients for five symptoms (kappa>0.4, P<0.005), including dyspnoea, cough, dry mouth, constipation and insomnia. For physicians, good agreement was found for three symptoms only, including pain, dyspnoea and cough. Moreover, physicians tended to underrate the distress. CONCLUSION: Fatigue, cachexia and anorexia were the three most distressful symptoms in the last week of life in this group of patients, but caregivers and physicians failed to rate them in agreement with patients.

Therapeutic effects and possible mechanisms of a snake venom preparation in the fibrotic rat liver.

The effects of a Chinese snake venom preparation from Agkistrodon halys pallas, used for treatment of hepatic fibrosis/cirrhosis in China, was investigated in an in vivo rat model and using in situ hepatic perfusion. Four groups were used in the experiments: (i) healthy, (ii) healthy/venom-treated, (iii) carbon tetrachloride (CCl4)-treated, and (iv) CCl4/venom-treated. Treatment effects were assessed by determining hepatic histopathology, biochemistry and fibrosis index parameters, bile production, biliary taurocholate recovery, hepatic mRNA expression of four bile salt transporters (Ntcp, Bsep, Oatp-1, and Oatp-3), comparison of hepatic microcirculation, fibrinolytic activity, and antithrombotic effects. Liver histopathology, biochemistry, and fibrosis index showed a dramatic improvement in venom-treated animals. There were significant differences in bile production between healthy/venom-treated and all other experimental groups and between CCl4/venom-treated and CCl4-treated animals, but no significant differences were found between CCl4/venom-treated and healthy animals. Biliary taurocholate recovery was significantly increased in healthy/venom-treated and CCl4/venom-treated animals. The expression of mRNA levels of the four bile salt transporters showed an increase after venom treatment. The hepatic microcirculation studies showed normalized sinusoidal beds in CCl4/venom-treated animals compared to healthy animals, whereas CCl4-treated animals showed abnormal profiles to the healthy and the CCl4/AHPV-treated animals. The fibrinogen and plasma thromboxane B2 levels of healthy rats decreased with increasing dose after venom treatment. It was concluded that snake venom treatment may be therapeutic in treatment of hepatic fibrosis/cirrhosis by possibly a combination of increased bile flow and improved hepatic microcirculation, changes in bile salt transporter expression, and fibrinolytic and antithrombotic effects of the snake venom preparation.

Hepatic pharmacokinetics of taurocholate in the normal and cholestatic rat liver.

The disposition kinetics of [3H]taurocholate ([3H]TC) in perfused normal and cholestatic rat livers were studied using the multiple indicator dilution technique and several physiologically based pharmacokinetic models. The serum biochemistry levels, the outflow profiles and biliary recovery of [3H]TC were measured in three experimental groups: (i) control; (ii) 17 alpha-ethynylestradiol (EE)-treated (low dose); and (iii) EE-treated (high dose) rats. EE treatment caused cholestasis in a dose-dependent manner. A hepatobiliary TC transport model, which recognizes capillary mixing, active cellular uptake, and active efflux into bile and plasma described the disposition of [3H]TC in the normal and cholestatic livers better than the other pharmacokinetic models. An estimated five- and 18-fold decrease in biliary elimination rate constant, 1.7- and 2.7-fold increase in hepatocyte to plasma efflux rate constant, and 1.8- and 2.8-fold decrease in [3H]TC biliary recovery ratio was found in moderate and severe cholestasis, respectively, relative to normal. There were good correlations between the predicted and observed pharmacokinetic parameters of [3H]TC based on liver pathophysiology (e.g. serum bilirubin level and biliary excretion of [3H]TC). In conclusion, these results show that altered hepatic TC pharmacokinetics in cholestatic rat livers can be correlated with the relevant changes in liver pathophysiology in cholestasis.

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein.

Nonalcoholic fatty liver disease is the most common of all liver diseases. The hepatic disposition [(3)H]palmitate and its low-molecular-weight metabolites in perfused normal and steatotic rat liver were studied using the multiple indicator dilution technique and a physiologically based slow diffusion/bound pharmacokinetic model. The steatotic rat model was established by administration of 17 alpha-ethynylestradiol to female Wistar rats. Serum biochemistry markers and histology of treated and normal animals were assessed and indicated the presence of steatosis in the treatment group. The steatotic group showed a significantly higher alanine aminotransferase-to-aspartate aminotransferase ratio, lower levels of liver fatty acid binding protein and cytochrome P-450, as well as microvesicular steatosis with an enlargement of sinusoidal space. Hepatic extraction for unchanged [(3)H]palmitate and production of low-molecular-weight metabolites were found to be significantly decreased in steatotic animals. Pharmacokinetic analysis suggested that the reduced extraction and sequestration for palmitate and its metabolites was mainly attributed to a reduction in liver fatty acid binding protein in steatosis.

Disposition kinetics of propranolol isomers in the perfused rat liver.

The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)-propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S()-propranolol differs from the R(+)-isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.

Ion-trapping, microsomal binding, and unbound drug distribution in the hepatic retention of basic drugs.

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pKa values of drugs. Lipophilicity and pKa determined hepatic drug retention: a drug with low pKa and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pKa and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pKa and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pKa basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites.

Disposition kinetics of [(3)H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [(3)H]palmitate and its low-molecular-weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [(3)H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. A slow-diffusion/bound model was found to better describe the hepatic disposition of unchanged [(3)H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female > clofibrate-treated male > female > male. Levels of other intrahepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low-molecular-weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [(3)H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [(3)H]palmitate and its low-molecular-weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intrahepatic proteins.

Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver.

Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl(4)-treated group (phenobarbital with CCl(4) treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of (3)H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl(4)-treated rats were found to have the smallest vascular space, extravascular albumin space, (3)H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of (3)H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses.

Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug.

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl(4))-induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)-acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P(app)) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl(4)-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P(app) or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.