Hepatocellular Necrosis, Fibrosis and Microsomal Activity Determine the Hepatic Pharmacokinetics of Basic Drugs in Right-Heart-Failure-Induced Liver Damage

Robertson, Thomas A.; Zhang, Qian; Fletcher, Linda M.; Crawford, Darrell H. G.; Weiß, Michael; Roberts, Michael S.

doi:10.1007/s11095-012-0690-z

Cited by 11 publications

(5 citation statements)

References 38 publications

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“…Both reversible and fatal cases of DILI from labetalol have been reported . Labetalol is metabolised predominantly by glucuronosyl transferase, and PK data in rats suggest that in NASH, CYP P450 induction leads to increased hepatic removal of labetalol and other cationic beta blockers (e.g.…”

Section: Resultsmentioning

confidence: 99%

Review article: prescribing medications in patients with cirrhosis – a practical guide

Lewis

Stine

2013

Aliment Pharmacol Ther

171

161

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Summary Background Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes. Aim To provide a practical approach to prescribing medications for cirrhotic patients. Methods An indexed MEDLINE search was conducted using keywords cirrhosis, drug‐induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed. Results Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2–3 g or less/day) for short durations, and is recommended as first‐line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care. Conclusions Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided.

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Section: Resultsmentioning

confidence: 99%

Review article: prescribing medications in patients with cirrhosis – a practical guide

Lewis

Stine

2013

Aliment Pharmacol Ther

171

161

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“…In addition to the immaturity of kidney function in young infants, right-sided heart failure accompanied with PAH may result in decreased eGFR. On the other hand, Li et al 27 reported that liver sections from rats with right heart failure showed serious central lobular necrosis and sinusoid dilation and that CYP concentration significantly decreased in the livers of rats with right heart failure. Therefore, various factors might have affected CL int in the present data analysis.…”

Section: Discussionmentioning

confidence: 99%

Plasma Concentrations of Tadalafil in Children With Pulmonary Arterial Hypertension

Kohno¹,

Ichida²,

Hirono³

et al. 2014

Therapeutic Drug Monitoring

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We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

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“…Right‐sided heart failure or obstruction of the cranial vena cava leads to increased central venous pressure and passive venous hepatic congestion. Liver perfusion is impaired, and ischemia and necrosis occur . Chronically, this can lead to centrilobular fibrosis.…”

Section: Causes Of Hepatic Fibrosis In Dogsmentioning

confidence: 99%

“…Liver perfusion is impaired, and ischemia and necrosis occur. 98 Chronically, this can lead to centrilobular fibrosis. A similar pattern can develop after toxin ingestion.…”

Section: Causes Of Hepatic Fibrosis In Dogsmentioning

confidence: 99%

Hepatic Fibrosis in Dogs

Eulenberg

Lidbury

2017

Veterinary Internal Medicne

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Hepatic fibrosis is commonly diagnosed in dogs, often as a sequela to chronic hepatitis (CH). The development of fibrosis is a crucial event in the progression of hepatic disease that is of prognostic value. The pathophysiology of hepatic fibrosis in human patients and rodent models has been studied extensively. Although less is known about this process in dogs, evidence suggests that fibrogenic mechanisms are similar between species and that activation of hepatic stellate cells is a key step. Diagnosis and staging of hepatic fibrosis in dogs requires histopathological examination of a liver biopsy specimen. However, performing a liver biopsy is invasive and assessment of fibrotic stage is complicated by the absence of a universally accepted staging scheme in veterinary medicine. Serum biomarkers that can discriminate among different fibrosis stages are used in human patients, but such markers must be more completely evaluated in dogs before clinical use. When successful treatment of its underlying cause is feasible, reversal of hepatic fibrosis has been shown to be possible in rodent models and human patients. Reversal of fibrosis has not been well documented in dogs, but successful treatment of CH is possible. In human medicine, better understanding of the pathomechanisms of hepatic fibrosis is leading to the development of novel treatment strategies. In time, these may be applied to dogs. This article comparatively reviews the pathogenesis of hepatic fibrosis, its diagnosis, and its treatment in dogs.

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Hepatocellular Necrosis, Fibrosis and Microsomal Activity Determine the Hepatic Pharmacokinetics of Basic Drugs in Right-Heart-Failure-Induced Liver Damage

Abstract: Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.

Cited by 11 publications

References 38 publications

Review article: prescribing medications in patients with cirrhosis – a practical guide

Review article: prescribing medications in patients with cirrhosis – a practical guide

Plasma Concentrations of Tadalafil in Children With Pulmonary Arterial Hypertension

Hepatic Fibrosis in Dogs

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