Is glucuronidation truly preserved in patients with liver disease?

Hoyumpa, Anastacio M.; Schenker, Steven

doi:10.1002/hep.1840130428

Cited by 75 publications

(27 citation statements)

References 85 publications

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“…Extrahepatic glucuronidation appears to contribute substantially to the overall clearance. [11][12][13][14][15][16] These characteristics of ranirestat metabolism suggest that the PK of ranirestat is not affected by hepatic impairment, in agreement with the findings of this clinical study that most ranirestat PK parameters, such as C max , t 1 2 , CL/F, Vz/F, and AUCs, in patients with mild and moderate hepatic impairment were similar to those observed in matched healthy subjects. It was reported that there were important differences in the frequency of UGT1A1 variant alleles across populations of different ethnicities.…”

Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment

Itou¹,

Fujita

Inoue

et al. 2020

The Journal of Clinical Pharma

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Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open‐label, single‐dose, parallel‐group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration‐time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.

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Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and Safety of Ranirestat in Patients With Hepatic Impairment

Itou¹,

Fujita

Inoue

et al. 2020

The Journal of Clinical Pharma

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“…However, drugs like venlafaxine are profoundly metabolised to a significant extent by the liver and, accordingly, a normal liver function is a prerequisite for normal pharmacokinetics and thus adequate dosing of the drug. Chronic liver disease results in an impaired drug metabolic capacity and it has been suggested that the phase I reactions are more affected than the phase II reactions in liver disease (Hoyumpa & Schenker 1991). This has led to the firm recommendation at present of lowering the dose of venlafaxine in cases of liver impairment (Ellingrod & Perry 1994;Holliday & Benfield 1995), including situations with chronic PCS.…”

mentioning

confidence: 99%

Open‐Field Behavioural Alterations in Liver‐Impaired and Sham‐Operated Rats after Acute Exposure to the Antidepressant Venlafaxine

Kugelberg

Apelqvist

Wikell

et al. 2005

Basic Clin Pharma Tox

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Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver-impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham-operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this ''normalisation'' in pharmacokinetics of the portacaval-shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open-field behaviour. Thus, portacaval-shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham-operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine-treated portacaval-shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine-treated sham rats, indicating an increase in central arena activity as compared to the sham-saline and portacaval-shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open-field behavioural studies in which both central and peripheral activities are recorded for measurement of open-field behavioural drug effects.

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“…However, this finding was not unexpected owing to the small sample size in the study. Metabolism via glucuronidation is less affected by mildto-moderate hepatic dysfunction compared with metabolism by cytochrome P450 isoenzymes [18][19][20]. A potential mechanism responsible for preserving glucuronidation may be an upregulation of UGT enzyme content in remaining viable hepatocytes as a response to liver injury, especially in those with cirrhosis [19].…”

Section: Discussionmentioning

confidence: 99%

“…A potential mechanism responsible for preserving glucuronidation may be an upregulation of UGT enzyme content in remaining viable hepatocytes as a response to liver injury, especially in those with cirrhosis [19]. Extrahepatic glucuronidation, as well as the deeper location of glucuronosyltransferases within the microsomal membrane, may also help preserve metabolism via glucuronidation [18,21]. One notable example of this is morphine; studies have shown that the glucuronidation of morphine remains preserved and the plasma clearance of morphine was not changed in subjects with cirrhosis [18].…”

Section: Discussionmentioning

confidence: 99%

“…Extrahepatic glucuronidation, as well as the deeper location of glucuronosyltransferases within the microsomal membrane, may also help preserve metabolism via glucuronidation [18,21]. One notable example of this is morphine; studies have shown that the glucuronidation of morphine remains preserved and the plasma clearance of morphine was not changed in subjects with cirrhosis [18]. The reduced A204-4455 AUC inf and AUC last in the mild HI group may be owing to the diminished activity of several UGT enzymes (specifically 1A3, 1A4, and 2B7) secondary to the chronic hepatitis, rather than cirrhosis, which was more prevalent in the moderate HI group.…”

Section: Discussionmentioning

confidence: 99%

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