Garcinia mangostana and α-Mangostin Revive Ulcerative Colitis-Modified Hepatic Cytochrome P450 Profiles in Mice.

<b>Background and Objective:</b> Ulcerative colitis (UC) is inflammation of the large intestine with ulceration but can also cause extraintestinal manifestations (EIM) by damaging surrounding organs such as the liver. <i>Garcinia mangostana</i> (GM) pericarp and α-mangostin (MGS) have been reported to have anti-inflammatory activity. This study evaluated the effects of GM pericarp extract and MGS on the expression of hepatic cytochrome P450 (CYP) enzymes as an EIM of UC. <b>Materials and Methods:</b> Male ICR mice were orally administered GM pericarp extract (40, 200 and 1000 mg/kg/day), MGS (30 mg/kg/day) or sulfasalazine (SUL) (100 mg/kg/day) daily for 7 days. On days 4-7, UC was induced by dextran sulfate sodium (DSS 40 kDa, 6 g/kg/day). Profiles of CYP mRNA expression were determined by RT/qPCR. Alkoxyresorufin <i>O</i>-dealkylation (including ethoxy-, methoxy-, pentoxy- and benzyloxy-resorufin), aniline hydroxylation and erythromycin <i>N</i>-demethylation CYP responsive activities were also examined. <b>Results:</b> The DSS-induced UC mice showed suppressed expression<i> </i>of <i>Cyp1a1</i>, <i>Cyp1a2</i>, <i>Cyp2b9/10</i>, <i>Cyp2e1</i>, <i>Cyp2c29</i>, <i>Cyp2d9</i>, <i>Cyp3a11</i> and <i>Cyp3a13</i> mRNAs. The GM pericarp extract and MGS restored expression of all investigated CYPs and their responsive enzyme activities in DSS-induced UC mice to levels comparable to the control and parallel to the effects of the anti-inflammatory control SUL. <b>Conclusion:</b> The GM is a promising therapy to restore UC-modified hepatic CYP profiles.

Physical Performance and Quality of Life in Older Adults: Is There Any Association between Them and Potential Drug Interactions in Polymedicated Octogenarians.

Older adults are at increased risk of several cytochrome P450 (CYP) drug interactions that can result in drug toxicity, reduced pharmacological effect, and adverse drug reactions. This study aimed to assess the prevalence of potential CYP interactions referring to the most clinically relevant drugs and exploring the relationship between them and quality of life and physical performance in Spanish octogenarians. Institutionalized and community-dwelling octogenarians (n = 102) treated at three primary care centers, were recruited by a research nurse. Anthropometric measurements, chronic diseases, prescribed drugs, quality of life, physical performance, mobility skills, hand grip strength and cognitive status data were collected. Potential CYP drug-drug interactions (DDIs) were selected referring to the main CYP implicated in their metabolism. The 72.2% of recruited octogenarians presented potentially inappropriate CYP inhibitor-substrate or CYP inductor-substrate combinations. Analyzing the EuroQol Visual Analogue scale (EQ-VAS) results, patients with a potential CYP DDI perceived worse health status than patients without it (p = 0.004). In addition, patients with a potential CYP DDI presented worse exercise capacity, kinesthetic abilities, or mobility than those who didn't present a potential interaction (p = 0.01, p = 0.047, and p = 0.02, respectively). To investigate and control factors associated with loss of muscle strength and poor quality of life, polypharmacy and DDIs could help institutions in the management of physical frailty.

Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation.

BACKGROUND: Cytochrome P450 inhibition by proton pump inhibitors (PPIs) may attenuate the effectiveness of clopidogrel. AIM: To examine whether PPI use modifies the association between clopidogrel use and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) with stent implantation, using time-varying drug exposure ascertainment. METHODS: We conducted this population-based cohort study in Western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and ascertained their reported comorbidities. During the recommended 12-month postintervention treatment period, we tracked use of clopidogrel and PPI and the rate of MACE. We used Cox regression to compute hazard ratios (HRs), controlling for potential confounders. RESULTS: During follow-up, one or more prescriptions were redeemed by 91% of patients for clopidogrel and by 21% of patients for PPIs. Of the patients, 15% experienced a MACE. The adjusted HR for MACE comparing clopidogrel use with non-use was 0.57 [95% confidence interval (CI): 0.44-0.74] among PPI users and 0.47 (95% CI: 0.42-0.53) among PPI non-users, yielding an interaction effect (i.e. relative rate increase) of 1.20 (95% CI: 0.91-1.58). PPI users treated from before PCI had a 25% increased rate of MACE compared to PPI non-users, independent of clopidogrel use [adjusted HR = 1.24 (95% CI: 0.97-1.58) for clopidogrel users and 1.26 (95% CI: 0.97-1.63) for clopidogrel non-users]. CONCLUSIONS: The use of PPIs as a class did not modify the protective effect of clopidogrel, but its use was associated with major adverse cardiovascular events itself, particularly among patients having used PPIs before percutaneous coronary intervention.

Grapefruit-drug interactions.

Grapefruit juice and grapefruit product consumption have potential health benefits; however, their intake is also associated with interactions with certain drugs, including calcium channel blockers, immunosuppressants and antihistamines. The primary mechanism through which interactions are mediated is mechanism-based intestinal cytochrome P450 3A4 inhibition by furanocoumarins resulting in increased bioavailability of administered medications that are substrates. Grapefruit products have also been associated with interactions with P-glycoprotein (P-gp) and uptake transporters (e.g. organic anion-transporting polypeptides [OATPs]). Polyphenolic compounds such as flavonoids have been proposed as the causative agents of the P-gp and OATP interactions. The mechanisms and magnitudes of the interactions can be influenced by the concentrations of furanocoumarins and flavonoids in the grapefruit product, the volume of juice consumed, and the inherent variability of specific enzymes and transporter components in humans. It is therefore challenging to predict the extent of grapefruit product-drug interactions and to compare available in vitro and in vivo data. The clinical significance of such interactions also depends on the disposition and toxicity profile of the drug being administered. The aim of this review is to outline the mechanisms of grapefruit-drug interactions and present a comprehensive summary of those agents affected and whether they are likely to be of clinical relevance.

Cytochrome P450 epoxygenase gene function in hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling.

We assessed pulmonary cytochrome P450 (CYP) epoxygenase expression and activity during hypoxia and explored the effects of modulating epoxygenase activity on pulmonary hypertension. The acute hypoxic vasoconstrictor response was studied in Swiss Webster mice, who express CYP2C29 in their lungs. Animals were pretreated with vehicle, the epoxygenase inhibitor (N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide) or an inhibitor of the soluble epoxide hydrolase. Whereas the epoxygenase inhibitor attenuated hypoxic pulmonary constriction (by 52%), the soluble epoxide hydrolase inhibitor enhanced the response (by 39%), indicating that CYP epoxygenase-derived epoxyeicosatrienoic acids elicit pulmonary vasoconstriction. Aerosol gene transfer of recombinant adenovirus containing the human CYP2C9 significantly elevated mean pulmonary artery pressure and total pulmonary resistance indices, both of which were sensitive to the inhibitor sulfaphenazole. The prolonged exposure of mice to hypoxia increased CYP2C29 expression, and transcript levels increased 5-fold after exposure to normobaric hypoxia (FIO2 0.07) for 2 hours. This was followed by a 2-fold increase in protein expression and by a significant increase in epoxyeicosatrienoic acid production after 24 hours. Chronic hypoxia (7 days) elicited pulmonary hypertension and pulmonary vascular remodeling, effects that were significantly attenuated in animals continually treated with N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide (-46% and -55%, respectively). Our results indicate that endogenously generated epoxygenase products are associated with hypoxic pulmonary hypertension in mice and that selective epoxygenase inhibition significantly reduces acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary vascular remodeling. These observations indicate potential novel targets for the treatment of pulmonary hypertension and highlight a pivotal role for CYP epoxygenases in pulmonary responses to hypoxia.

CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.

Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolic activation of several procarcinogens including dietary and environmental nitrosamines, and the involvement of CYP2A6 in cancer development has been postulated. CYP2A6 phenotype was determined using caffeine as a probe drug in individuals participating in a case-control study of colorectal cancer (127 cases and 333 controls matched on age, gender, race, and geographic region). Conversion of the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyl uric acid (17U) is catalyzed primarily by CYP2A6, and this activity can be assayed by comparison of urinary molar ratios of metabolites. Caffeine (200 mg) was administered to each participant, and a 4-5 h postadministration urine sample was collected. Urinary metabolites of caffeine were separated by high-performance liquid chromatography and quantified by comparison to authentic standards. We examined the distributions of the ratio, 17U:17X, according to subject characteristics among controls. In case-control comparisons, subjects in the medium and high tertiles of CYP2A6 activity had an increased risk of colorectal cancer compared with subjects with low activity. Odds ratios from a conditional logistic regression model for medium and high 17U:17X ratio were 2.0 (95% confidence interval, 1.1-3.7) and 2.6 (95% confidence interval, 1.5-4.5), respectively (P for trend = 0.001). CYP2A6 phenotype has not been compared previously between cancer cases and controls. We found a strong relationship between CYP2A6 activity, measured by urinary caffeine metabolite ratio, and colorectal cancer risk.

[Drug interactions with antiretroviral agents]. / Interactions médicamenteuses avec les antirétroviraux.

Concomitant administration of three or more antiretroviral drugs is the standard treatment for HIV-infected patients. I.p. and NNRT are metabolized by cytochrome P450 and are inhibitors or inducers of CYP3A4. Therefore a number of drug-drug interactions are likely to occur. Ritonavir, a potent CYP3A4 inhibitor, is coadministered with saquinavir, indinavir and amprenavir to enhance their plasma concentrations and their virological efficacy. In contrast, nevirapine and efavirenz are CYP3A4 inducers, which warrant an increase in i.p. dosing. These properties lead to interactions with other drugs metabolized by CYP3A4 and a knowledge or the route of biotransformation is useful to avoid side-effects or decrease efficacy (as in the case of statine coadministration). Some important interactions can lead to contraindications such as coadministration of rifampicine, astemizole, ergot derivates or cizapride, as a large decrease or increase in concentration can lead to inefficacy or to major side-effects. Clinical trials and notification of side-effects are important to detect unpredictable interactions and to propose guidelines; such an example is therapeutic drug monitoring of methadone to avoid withdrawal syndrome when coadministered with ritonavir or nelfinavir.

What should the clinician know about the cytochrome P450 system?

The cytochromes P450 are a superfamily of enzymes which catalyse mono-oxidation, thus transforming fat-soluble toxins into water-soluble metabolites which are excreted in urine. Cytochromes P450 are mainly located in the liver, they play a major role in hepatotoxicity. The toxins (or the drugs) can be in part transformed into reactive metabolites which destroy intrahepatocytic proteins (metabolite-related hepatotoxicity) or form an immune complex that induces immune reactions (immune-related hepatotoxicity).

The role of CYP enzymes in cocaine-induced liver damage.

Cocaine is hepatotoxic in several species, including man. A high dose of cocaine produces metabolism-dependent, mainly pericentral, liver damage. At 24 h after a single dose of cocaine, mouse hepatic P450 content decreases but CYP2A activities; coumarin 7-hydroxylase and testosterone 15 alpha-hydroxylase increase concomitant with prominent diffuse cell necrosis. Repeated administration of cocaine for up to 5 days decreases CYP1A1/2, 2A4/5, 2Cx, and 2E1 related enzymatic activities. However, after five doses of cocaine, CYP2B10 increases in conjunction with the healing process. In the acute phase, the increased CYP2A activities do not participate in cocaine bioactivation. CYP3A enzymes are principally responsible for the cocaine N-demethylation in human and mouse liver microsomes. The hepatic metabolic CYP enzyme profile will change during prolonged cocaine intake, this being accompanied by altered cell morphology. Possible connections to cocaine toxicity in man are discussed.