Conjugation pathways in liver disease.

Pacifici, Gian Maria; Viani, A; Franchi, M; Santerini, Sabrina; Temellini, A.; Giuliani, L.; Carrai, Maura

doi:10.1111/j.1365-2125.1990.tb03794.x

Cited by 31 publications

(12 citation statements)

References 22 publications

(23 reference statements)

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“…A fraction of a delafloxacin dose is conjugated by the liver into glucuronidated metabolites for excretion by the kidneys, and this process is facilitated through the liver . However, unlike hepatic metabolism through the cytochrome P450 system, phase 2 conjugation by the liver is rarely impacted by hepatic disease until there is severe damage . Therefore, one might predict that hepatic disease would not be a major factor in the disposition of delafloxacin and its glucuronide metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…13 However, unlike hepatic metabolism through the cytochrome P450 system, phase 2 conjugation by the liver is rarely impacted by hepatic disease until there is severe damage. 14,15 Therefore, one might predict that hepatic disease would not be a major factor in the disposition of delafloxacin and its glucuronide metabolites. However, because a large percentage of delafloxacin is cleared by the kidneys (ß65%), whether as intact molecule or the conjugated metabolites, we also could have a confounding variable in subjects with varying degrees of renal function.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram‐positive, Gram‐negative, atypical, and anaerobic bacteria, including methicillin‐resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community‐acquired pneumonia. This was a phase 1, open‐label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child‐Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log‐transformed values for AUC0‐∞, Cmax, and systemic clearance, with hepatic group as a fixed effect. Mean AUC0‐∞ and Cmax in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least‐squares means of AUC0‐∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child‐Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child‐Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child‐Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hoover¹,

Marbury

Preston

et al. 2016

The Journal of Clinical Pharma

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“…Many drugs induce a significant release of more unconjugated fraction with chronic liver disease; such drugs may be metabolized more rapidly in patients with cirrhosis (Delcò et al, 2005). However, Pacifici et al (1990) demonstrated that liver disease reduces the activities of sulfotransferase, acetyltransferase, glutathionetransferase, and thiomethyltransferase. The plasma AUC of unconjugated silibinin was significantly reduced in the presence of liver cirrhosis, which might be due to a decrease in the enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

Hepatobiliary Excretion of Silibinin in Normal and Liver Cirrhotic Rats

Wu¹,

Lin

Hung

et al. 2007

Drug Metab Dispos

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ABSTRACT:Silibinin is the main biologically active flavonolignan extracted from the seeds and fruits of milk thistle and has potential efficacy in the treatment of liver disease. The aim of the present study was to examine the hepatobiliary excretion of silibinin and its effect on dimethylnitrosamine (DMN)-induced liver cirrhosis. The experiments were divided into five groups: 10, 30, and 50 mg/kg silibinin alone, 30 mg/kg silibinin coadministered with cyclosporin A (CsA), and 50 mg/kg silibinin with liver cirrhosis induced by DMN. The data indicated that silibinin had dose-related pharmacokinetics in the dose ranges of 10 to 50 mg/kg. All of the unconjugated or total (unconjugated ؉ conjugated) silibinin concentrations in the bile were significantly higher than those in plasma at the sampling time points at each dose, suggesting active hepatobiliary excretion. When coadministered with CsA, the area under the concentration versus time curve (AUC) in bile was significantly decreased. This result suggested that the active silibinin efflux might be partially inhibited by P-glycoprotein. In the DMN-induced liver cirrhotic rats, the AUC of plasma unconjugated silibinin was reduced by 53%; however, total silibinin was increased by 182%. These results together suggest that the phase II conjugative reaction of silibinin was blocked by treatment with DNM.

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“…[Figure 3 near here] [Table 4 near here] Among Phase 2 reactions, sulfation reactions are more notably affected by liver injury, when compared to glucuronidation [Elbekai et al , 2004]. Historically glucuronidation has been viewed as being spared by the effects of hepatic impairment [Pacifici et al , 1990, Choo et al , 1999, Verbeeck, 2008], but there has been more evidence that suggests that effects on glucuronidation maybe significant in severe liver impairment and for drugs undergoing ester, as opposed to ether, glucoronidation (e.g., zidovudine) [Brouwer et al , 1992]. …”

Section: Impact On Pharmacokinetic Processesmentioning

confidence: 99%

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Büdingen

González

Tucker

et al. 2014

Therapeutic Advances in Infection

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The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, such as Cmax/MIC, AUC/MIC, T>MIC, IC50/EC50, or T>EC95. Loss of efficacy, or conversely, increased risk of toxicity may occur in certain circumstances of liver injury. Although important to consider these potential alterations and their effects on specific anti-infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy.

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Conjugation pathways in liver disease.

Cited by 31 publications

References 22 publications

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment

Hepatobiliary Excretion of Silibinin in Normal and Liver Cirrhotic Rats

Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

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