Comorbidities associated with nonalcoholic fatty liver often require therapy with medications (eg, statins) metabolized by cytochrome P-450 3A (CYP3A). There is significant interindividual variability in CYP3A expression. However, human studies that systematically examined the relationship between hepatic steatosis and hepatic CYP3A activity are lacking.
The relationship of hepatic CYP3A activity with several variables including hepatic steatosis, CYP3A4 protein content, CYP3A4 mRNA expression, CYP3A5 genotype, and its mRNA expression was investigated in human liver samples (n = 49). CYP3A activity was quantified from liver microsomes by using testosterone as a probe, and hepatic steatosis was defined to be present if >5% of hepatocytes had large globules of intracellular fat displacing the nucleus.
The mean +/- standard error hepatic CYP3A activity of the study group was 3156 +/- 2794 pmol x min(-1) x mg(-1) of protein, and it was not associated with age, gender, medicinal use, CYP3A5 or pregnane xenobiotic receptor mRNA expression, or CYP3A5 genotype. Twenty-four liver samples with steatosis had significantly lower hepatic CYP3A activity than 25 liver samples without steatosis (1978 +/- 299 vs 4287 +/- 659 pmol x min(-1) x mg(-1) of protein; P = .003). This difference persisted even after controlling for relevant covariates in the multivariate analysis (P = .04). However, CYP3A4 protein content was not different between the 2 groups (6 +/- 1.3 vs 8.5 +/- 2.2 pmol/mg protein; P = .3). There was a significant negative relationship between severity of steatosis and hepatic CYP3A activity (P = .01).
Hepatic steatosis is associated with decreased hepatic CYP3A activity in humans via post-translational mechanism. Further studies are needed to confirm our findings.
"As with most drug–drug interaction studies, healthy volunteers, rather than patients, were enrolled in this study. MVC is primarily metabolized by the liver and therefore exposures have the potential to be higher in HIV/HCV coinfected patients with hepatic impairment, as hepatic damage and disease may affect CYP enzyme activity.27–32 A study conducted in HIV-negative subjects with hepatic impairment demonstrated that MVC exposures in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment had a geometric mean 25% (mild) and 46% (moderate) greater AUClast and a 11% (mild) and 32% (moderate) greater Cmax relative to subjects with normal hepatic function33 after a single dose of MVC 300 mg. "
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effects of boceprevir (BOC) and telaprevir (TVR) on the pharmacokinetics (PK) of maraviroc (MVC) in healthy volunteers.
In this open-label, fixed-sequence study, 14 volunteers received MVC 150 mg twice-daily (BID) alone for 5 days (Period 1), followed by MVC+BOC 800 mg three-times-daily (TID) and MVC+TVR 750 mg TID, each for 10 days in Periods 2 and 3, respectively, with a ≥10-day wash-out. PK was analyzed on Day 5 of Period 1 and Day 10 of Periods 2 and 3. Safety was also assessed.
Ratios of the adjusted geometric means (90% confidence intervals) for MVC area under the curve from pre-dose to 12 hours, maximum plasma concentration, and plasma concentration at 12 hours were 3.02 (2.53-3.59), 3.33 (2.54-4.36), and 2.78 (2.40-3.23), respectively, for MVC+BOC versus MVC alone, and 9.49 (7.94-11.34), 7.81 (5.92-10.32), and 10.17 (8.73-11.85), respectively, for MVC+TVR versus MVC alone. PK profiles for MVC+BOC or TVR were consistent with historic values for BOC and TVR monotherapy. Adverse event incidence was higher with MVC+BOC and MVC+TVR versus MVC alone. Dysgeusia (50%) and pruritus (29%) occurred most commonly with MVC+BOC, and fatigue (46%) and headache (31%) with MVC+TVR. There were no serious adverse events.
MVC exposures were significantly increased with BOC or TVR, therefore MVC should be dosed at 150 mg BID when co-administered with these newly approved hepatitis C protease inhibitors. No dose adjustment for BOC or TVR is warranted with MVC. MVC+BOC or TVR was generally well tolerated with no unexpected safety findings.
"This effect may be attributed to the ability of limonin to inhibit CYP3A4 activity (Iwata et al. 2005). Previous studies indicated that hepatic steatosis is associated with decreased hepatic CYP3A4 activity in humans via posttranslational mechanism (Kolwankar et al. 2007). "
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptors have been implicated in inflammation and injury in various tissues and organs including the liver. We have investigated the effects of limonin isolated from the dichloromethane fraction of the seeds of bittersweet orange (Citrus aurantium var. bigaradia) in two dose levels (50 and 100 mg/kg) against D-galactosamine (D-GalN)-induced liver toxicity in comparison with standard silymarin treatment on Toll-like receptors expression and hepatic injury, using a well-established rat model of acute hepatic inflammation. The limonoids in the seeds of bittersweet orange were identified. Oral administration of limonin before D-GalN injection, significantly attenuated markers of hepatic damage (elevated liver enzyme activities and total bilirubin) and hepatic inflammation (TNF-α, infiltration of neutrophils), oxidative stress and expression of TLR-4 but not TLR-2 in D-GalN-treated rats. Limonin effects were similar in most aspects to that of the lignan silymarin. The higher dose of limonin (100 mg/kg) performed numerically better for AST and bilirubin, and both doses yielded similar results for ALT and GGT. While the lower dose of limonin (50 mg/kg) performed better against oxidative stress and liver structural damage as compared to the higher dose. Limonin exerts protective effects on liver toxicity associated with inflammation and tissue injury via attenuation of inflammation and reduction of oxidative stress.
Archiv für Experimentelle Pathologie und Pharmakologie 11/2013; 387(3). DOI:10.1007/s00210-013-0937-1 · 2.47 Impact Factor
"Moreover, the CYP3A4 drug metabolizing activity is also a factor influencing inter-individual variability and hence, is relevant to NAFLD patients undergoing statin therapy. The level of CYP3A protein correlates negatively with the severity of steatosis in humans (Kolwankar et al., 2007). No changes were found in the CYP3A4 mRNA level in human fatty liver samples at various stages of NAFLD progression, however a trend of decreasing activity and protein levels was observed (Fisher et al., 2009b). "
[Show abstract][Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD.
Frontiers in Genetics 01/2013; 4:2. DOI:10.3389/fgene.2013.00002
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