Integrated care in cancer: What is it, how is it used and where are the gaps? A textual narrative literature synthesis.

Integrated care is an underpinning concept of contemporary health care policy proffered as a strategy to overcome the fragmentations in care encountered by people with complex care needs (Shaw et al. [2011] What is Integrated Care? An Overview of Integrated Care in the NHS). Cancer patients have potential to benefit from such policy, often having needs that extend beyond cancer. This paper seeks to understand how the concept of integrated care is used in the cancer literature. A search of leading databases was conducted for original research relating to integrated care or an integration intervention aiming to improve outcomes of cancer patients, and analysed using textual narrative synthesis. 38 papers were included, each with a focus on improving cancer-specific aspects of care enhancing the capabilities of the cancer multidisciplinary team. Of the eight studies involving integration between the cancer service and other care providers, all focused on utilising the external provider to deliver aspects of cancer care or placed them in a passive role, as survey participant, a recipient of cancer-related clinical information or as the comparator "usual care" arm. Within the cancer literature, integration is predominantly used to describe initiatives to improve cancer-related aspects of care. Less attention is given to integration initiatives that enhance coordination across levels of the healthcare system or service providers.

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. RESULTS: Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). INTERPRETATION: This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials.

BACKGROUND: Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance. METHODS: Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit. RESULTS: Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05). CONCLUSION: Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.

Exploration of the perceptions, barriers and drivers of pharmacogenomics practice among hospital pharmacists in Adelaide, South Australia.

There is little literature regarding the barriers to the uptake of pharmacogenomics (PG) in pharmacy practice, especially with respect to Australia. To date, pharmacists have seldom been engaged in discussions of these issues. This study aimed to obtain an in-depth understanding of these barriers by interviewing pharmacists in Adelaide, South Australia. Ethics approved semistructured interviews were carried out with 21 public hospital pharmacists. Analysis of the data identified themes including: confidence to engage in PG, clinician acceptance of a pharmacist PG role, and the importance of timely and relevant PG education. Interviewees thought that pharmacists could have a greater participation in PG in the future, but they questioned whether this would be possible at the moment given, among other factors, existing time and work constraints.

The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis.

To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Metabolism of food-derived heterocyclic amines in human and rabbit tissues by P4503A proteins in the presence of flavonoids.

The ability of human and rabbit gastrointestinal-tract microsomes to metabolize the heterocyclic amine 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) to a mutagen was determined with the Ames test. When human jejunal and ileal microsomes were used as the metabolic activation source, MeIQ produced 1675 and 388 revertants/mg of microsomal protein, respectively, and this increased to 29,230 and 17,963 revertants/mg of microsomal protein, respectively, in the presence of 100 microM alpha-naphthoflavone. MeIQ in the presence of control rabbit duodenal, jejunal, and ileal microsomes produced 2304 +/- 1018, 988 +/- 386, and 444 +/- 134 (mean +/- SD, four samples) revertants/mg of microsomal protein, respectively. In the presence of alpha-naphthoflavone (100 microM), these activities increased greater than 7-fold. P4503A proteins were detectable on Western blots of microsomes prepared from both human and rabbit small intestine. Further, rifampicin-induced rabbit hepatic-microsomal activation of MeIQ was completely inhibited at low concentrations of alpha-naphthoflavone, but at higher concentrations (i.e., 100 microM) this returned to control levels. Flavone also caused a marked stimulation of MeIQ activation in human and rabbit gastrointestinal-tract microsomes. The aforementioned data suggest that flavonoids markedly increase the ability of P4503A isozymes to activate heterocyclic amines to mutagens in the Ames test.

Polymorphic variations in the expression of the chemical detoxifying UDP glucuronosyltransferases.

The UDP glucuronosyltransferases (UGT) are expressed predominantly in the liver and gastrointestinal tract in humans. Their expression varies widely between individuals, due in part to coding region polymorphisms that alter catalytic function and in part, to differences in the regulation of UGT genes. The latter differences are most likely the result of polymorphisms in the regulatory elements of UGT genes and in the transcription factors that bind to these elements. Several frequent polymorphisms in the promoters of UGT genes have been described; however, few of these fall within critical regulatory elements and alter UGT expression. Some rare mutations alter UGT promoter activity in in vitro systems but their effect in the clinic is still to be confirmed. Several transcription factors that regulate UGT gene expression in cells of hepatic and intestinal origin have been identified. These include positive regulators of UGT gene expression such as hepatocyte nuclear factor 1 alpha (HNF1 alpha), octamer transcription factor-1 (Oct-1) and the intestine-specific transcription factor, caudal-related homeodomain protein 2 (Cdx2). Negative regulators include the Pre B cell homeobox factor (Pbx2) and its dimerization partner, Pbx regulating protein 1 (Prep1). Polymorphisms in these transcription factors may cause differences in their interaction and binding to UGT promoters. Current work describing the effects of these transcription factor polymorphisms on UGT expression will be described. Knowledge of UGT promoter elements and the proteins that bind to these elements, as well as knowledge of polymorphisms that alter their function, may aid in the prediction of an individual's response to chemicals and in the prediction of chemical toxicities.

Species-specific expression of CYP4B1 in rabbit and human gastrointestinal tissues.

CYP4B1 is a P450 enzyme displaying tissue and species specific regulation. The rabbit CYP4B1 enzyme exhibits activity towards procarcinogenic aromatic amines. In the present study, CYP4B1 expression has been characterized in rabbit tissues using histological techniques, Northern blotting and Western blotting. Similar analyses were attempted using available human tissues. CYP4B1 mRNA and protein was demonstrated throughout the rabbit small intestine and colon. A unique 1.8 kb transcript, that is smaller than the transcript found in other tissues, was detected in rabbit stomach with a CYP4B1 specific RNA probe. No CYP4B1 protein was detected in this tissue. In rabbit liver, CYP4B1 was induced by phenobarbital primarily in zone 1 hepatocytes (periportal). In humans, CYP4B1 expression was demonstrated at low levels in human colon using in situ hybridization but not in liver or the small intestine. All rabbit gastrointestinal tissues other than stomach possess a high capacity for the activation of 2-aminofluorene compatible with CYP4B1 expression. In contrast, no activity was observed in human gastrointestinal microsomes. The present study therefore shows that CYP4B1 is an abundant P450 in the rabbit gastrointestinal tract and identifies species-specific differences in CYP4B1 expression and function.

Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.

Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity.

Sensitivity of CYP1A1 mRNA inducibility by dioxin is the same in Cyp1a2(+/+) wild-type and Cyp1a2(-/-) null mutant mice.

In mammals, the induction of experimental porphyria by halogenated aromatic hydrocarbons (HAHs) seems to be influenced by the levels of hepatic CYP1A2. The pharmacokinetics and relative rates of uptake and storage of HAHs in the liver are correlated with hepatic CYP1A2 concentrations. It is possible that these rates of HAH uptake and storage might affect the expression of other HAH-inducible genes. The differential inducibility of liver CYP1A1 mRNA by dioxin was therefore compared in Cyp1a2(+/+) wild-type mice, Cyp1a2(+/-) heterozygotes, and Cyp1a2(-/-) homozygous null mutants. Using doses of dioxin over eight orders of magnitude (from 10[-12] to 10[-4] g/kg), we could detect no differences in the sensitivity of CYP1A1 mRNA inducibility. These data indicate that the complete absence of the microsomal CYP1A2 enzyme has no measurable effect on hepatic expression of the Cyp1a1, gene, the only other known member of the mammalian CYP1A cytochrome P450 subfamily.

Role of CYP2A5 and 2G1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the Cyp1a2(-/-) mouse.

Acetaminophen (AP) is a widely-used analgesic agent that has been linked to human liver and kidney disease with prolonged or high-dose usage. In rodents, the target organs that are affected include liver, kidney, and the olfactory mucosa. AP toxicity requires cytochrome P450(CYP)-mediated metabolic activation, and the isozymes CYP1A2, 2E1, and 3A are known to activate AP in the human. In the present study, we determined that olfactory mucosal toxicity of AP was not different between the Cyp1a2(+/+) wild-type and the Cyp1a2(-/-) knockout mouse, whereas the hepatic toxicity of AP was significantly diminished in Cyp1a2(-/-) mice. Western blots of olfactory mucosa revealed that CYP2E1 and CYP3A levels are similar between untreated Cyp1a2(+/+) and Cyp1a2(-/-) mice. Diallyl sulfide (DAS), a known inhibitor of CYP2E1 and of CYP2A10/2A11 (the rabbit orthologue of mouse CYP2A5), completely eliminated olfactory toxicity of AP in both the Cyp1a2(-/-) and wild-type mouse olfactory mucosa. We found that heterologously expressed mouse CYP2A5 and CYP2G1 enzymes (known to be present in olfactory mucosa) form 3-hydroxyacetaminophen (3-OH-AP) and 3-(glutathion-S-yl)acetaminophen (GS-AP); CYP2A5 is considerably more active than 2G1. Addition of GSH caused increases in GS-AP proportional to decreases in 3-OH-AP, suggesting that these two metabolites arise from a common precursor or are formed by way of competing pathways. We also found that both CYP2A5 and CYP2G1 are inhibitable by DAS in vitro. These studies provide strong evidence that, in addition to CYP2E1, CYP2A5 and 2G1 are important in AP bioactivation in the mouse olfactory mucosa and that CYP1A2 appears to be of minor importance for AP olfactory toxicity.

Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer.

A growing number of human genetic polymorphisms in drug-metabolizing enzymes (DMEs) are being characterized. Some of these have been shown, quite convincingly, to be correlated with risk of toxicity or cancer, whereas others presently remain equivocal. There is good evidence that the correlation is stronger in populations exposed to a variety of environmental procarcinogens; perhaps 30% of DME substrates are able to be metabolically potentiated. Phase I DMEs, most of which represent cytochromes P450, metabolically activate procarcinogens to genotoxic electrophilic intermediates, and Phase II DMEs conjugate the intermediates to water-soluble derivatives, completing the detoxification cycle. It follows that genetic differences in the regulation, expression and activity of genes coding for Phase I and Phase II DMEs would be crucial factors in defining cancer susceptibility and the toxic or carcinogenic power of environmental chemicals. Not all Phase I and Phase II DMEs are implicated in detoxification; previous work from this and from other laboratories has identified candidate Phase I and Phase II genes in which certain alleles are more likely to be associated with cancer susceptibility. In some cases, the allelic frequencies vary dramatically between ethnic groups. In this review, our current knowledge about polymorphisms in the following genes are updated: the aromatic hydrocarbon receptor (AHR), the CYP1A1 structural gene (which encodes aryl hydrocarbon hydroxylase activity), the CYP1A2 structural gene (arylamine oxidations), the CYP2C19 gene (S-mephenytoin 4'-hydroxylase), the CYP2D6 gene (debrisoquine hydroxylase), the CYP2E1 gene (N,N-dimethylnitrosamine N-demethylase), the null mutant for the GSTM1 gene (glutathione transferase mu), and the NAT2 gene (arylamine N-acetyltransferase). If unequivocal biomarkers of genetic susceptibility to cancer and toxicity can be developed successfully, then identification of individuals at increased risk would be very helpful in the fields of public health and preventive medicine.

Towards integrated ADME prediction: past, present and future directions for modelling metabolism by UDP-glucuronosyltransferases.

Undesirable absorption, distribution, metabolism, excretion (ADME) properties are the cause of many drug development failures and this has led to the need to identify such problems earlier in the development process. This review highlights computational (in silico) approaches that have been used to identify the characteristics of ligands influencing molecular recognition and/or metabolism by the drug-metabolising enzyme UDP-gucuronosyltransferase (UGT). Current studies applying pharmacophore elucidation, 2D-quantitative structure metabolism relationships (2D-QSMR), 3D-quantitative structure metabolism relationships (3D-QSMR), and non-linear pattern recognition techniques such as artificial neural networks and support vector machines for modelling metabolism by UGT are reported. An assessment of the utility of in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters highlights the benefit of using multiple pharmacophores and also non-linear techniques for classification. Some of the challenges facing the development of generalisable models for predicting metabolism by UGT, including the need for screening of more diverse structures, are also outlined.

Human thiopurine methyltransferase: no evidence of activation by its substrates.

A HPLC assay was developed to assay baculovirus expressed human thiopurine methyltransferase activity. Using 6-mercaptopurine as substrate, the expressed thiopurine methyltransferase was found to have an apparent Km of 0.99 mM and a Vmax of 19 nmoles/mg/min. These values are in agreement with those determined using the standard radiometric assay for thiopurine methyltransferase activity. The effects of 6-thioguanine on 6-mercaptopurine metabolism were determined. 6-Thioguanine was found to be a mixed inhibitor of 6-mercaptopurine methylation.

Localization of cytochromes P450 in human tissues: implications for chemical toxicity.

Cytochromes P450 comprise a remarkably diverse superfamily of heme-thiolate proteins critical in the metabolism of numerous endogenous ligands and xenobiotics. Among the myriad of P450 substrates are many compounds of toxicological and pharmacological significance. The precise complement of cytochrome P450 isoforms in any given tissue may therefore be an important determinant of susceptibility to chemical-mediated toxicity. We have used a histological approach to study the distribution of individual P450s in human and rabbit gastro-intestinal tissues. We have focused primarily on P450 enzymes of importance in the metabolism of carcinogens, namely CYP1A1, CYP1A2, CYP2E1, CYP3A4/3A5 and CYP4B1. Here we give an overview of the distribution of these enzymes in human and rabbit tissues and discuss the possible toxicological implications of the results. In addition we will discuss the value of archival human tissue specimens for histological analysis of P450 distribution.

Metabolic differences in colon mucosal cells.

The colonic expression of cytochromes P450 from the CYP1A, CYP3A and CYP4B subfamilies has been characterized in rabbit and human tissues using RNA blotting, immunoblotting, immunohistochemistry and hybridization histochemistry. These studies demonstrate negligible expression of the CYP1A subfamily in either rabbit or human colon. The CYP3A6 gene is expressed in rabbit colon although at markedly reduced levels relative to liver and small intestine. Whilst at least two CYP3A genes are expressed at the mRNA level in human colon tissue from some individuals, no expression was demonstrated in others. Where expression was observed, this expression was continuous throughout the length of the colon. In rabbits, CYP4B1 represents a major colon P450 enzyme, expressed at levels in colon comparable to liver and small intestine. In contrast, the human CYP4B1 gene is expressed at low levels in some individuals. These studies highlight individual differences in the expression of cytochrome P450 enzymes of importance in procarcinogen metabolism.

The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies.

In both animal models and humans, the first and obligatory step in the activation of arylamines is N-hydroxylation. This pathway is primarily mediated by the phase-I enzymes CYP1A1, CYP1A2 and CYP4B1. In the presence of flavonoids such as alpha-naphthoflavone and flavone, both CYP3A4 and CYP3A5 have also been shown to play a minor role in the activation of food-derived heterocyclic amines. The further activation of N-hydroxyarylamines by phase-II metabolism can involve both N, O-acetylation and N, O-sulfonation catalyzed by N-acetyltransferases (NAT1 and NAT2) and sulfotransferases, respectively. Using an array of techniques, we have been unable to detect constitutive CYP1A expression in any segments of the human gastrointestinal tract. This is in contrast to the rabbit where CYP1A1 protein was readily detectable on immunoblots in microsomes prepared from the small intestine. In humans, CYP3A3/3A4 expression was detectable in the esophagus and all segments of the small intestine. Northern blot analysis of eleven human colons showed considerable heterogeneity in CYP3A mRNA between individuals, with the presence of two mRNA species in some subjects. Employing the technique of hybridization histochemistry (also known as in situ hybridization), CYP4B1 expression was observed in some human colons but not in the liver or the small intestine. Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract. NAT1 and NAT2 mRNA expression was detected in the human liver, small intestine, colon, esophagus, bladder, ureter, stomach and lung. Using a general aryl sulfotransferase riboprobe (HAST1), we have demonstrated marked sulfotransferase expression in the human colon, small intestine, lung, stomach and liver. These studies demonstrate that considerable variability exists in the expression of enzymes involved in the activation of aromatic amines in human tissues. The significance of these results in relation to a role for heterocyclic amines in colon cancer is discussed.

Hepatic microsomal enzyme activity in the koala and tammar wallaby: high 17beta-hydroxysteroid oxidoreductase activity in koala liver microsomes.

We have studied the hepatic microsomal xenobiotic metabolising capacity of koala (Phascolarctos cinereus) and tammar wallaby (Macropus eugenii). Total cytochrome P450 content in hepatic microsomes from koala (0.87 +/- 0.18 nmol/mg protein, n = 4, mean (S.D.) and rat were comparable while tammar wallaby displayed reduced P450 content (0.24 +/- 0.04 nmol/mg protein). Associated microsomal activities (NADPH cytochrome P450 reductase, aminopyrine N-demethylation, aniline hydroxylation, and androstenedione 6beta- and 16alpha-hydroxylation) in koala liver were similar to or reduced relative to rat. Hepatic microsomal NADPH-supported 17beta-hydroxysteroid oxidoreductase (17beta-HSOR) activity was significantly higher in koala (9.99+/-3.08 nmol/mg protein/min) than in tammar wallaby liver (0.86 +/- 0.16 nmol/mg protein/min). However, when NADH was utilised as cofactor the activity was similar in both marsupial species (koala, 1.44 +/- 0.84 nmol/mg protein/min; tammar wallaby, 1.52 +/- 0.44 nmol/mg protein/min). Michaelis-Menten parameters for the kinetics of 17beta-HSOR androstenedione reduction by NADPH and NADH were determined in the koala. The Km for androstenedione was of the order of 1.9-4 microM (n = 4) irrespective of the cofactor used, whilst the Km for NADPH was 0.04-0.05 microM (n = 2) and for NADH was 134-430 microM (n = 2). Potential inhibitors were evaluated for their effects on NADPH-mediated 17beta-HSOR activity with menadione and, to lesser extents, menthone, benzaldehyde and metyrapone eliciting significant inhibition. From detailed kinetic studies menthone was found to be an uncompetitive inhibitor of the activity in koala liver (Ki 220 microM).

Prasugrel vs. clopidogrel for cytochrome P450 2C19-genotyped subgroups: integration of the TRITON-TIMI 38 trial data.

BACKGROUND: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON-TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced-function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non-ST segment elevation myocardial infarction is currently uncertain. METHODS AND RESULTS: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON-TIMI 38 trial. Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39-0.83]. For CYP2C19 extensive metabolizers (∼70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80-1.20). CONCLUSIONS: Integration of the TRITON-TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.