The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone—a novel galactose single‐point method as a measure of residual liver function

Hu, Oliver Yoa Pu; Tang, Haoning; Chang, Ching‐Ling ‐L

doi:10.1002/bdd.2510150704

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…[68][69][70][71] Where the biliary elimination of unchanged drug was impaired, there was a concomitant increase in urinary excretion of unchanged drug.l [69][70][71] Another study concluded that the biliary elimination of the diacid metabolite of temocapril was not altered in cirrhosis; [72] however, impaired formation of the diacid metabolite may have obscured a reduction in its biliary elimination. In patients with advanced cirrhosis, the clearance of rocuronium was found to be the same as in healthy individuals.…”

Section: Biliary Excretionmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

192

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The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories. In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis. A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine. Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination. Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, 'safe' drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics. In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless...

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Section: Biliary Excretionmentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

192

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“…However, they often lack sensitivity in the early stages of liver diseases and change only in advanced stages. The galactose single-point (GSP) method has been recommended by the US Food and Drug Administration in the guidance document for the industry, "Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling," and has been successfully used to predict a variety of liver diseases (31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Shih

Young

Lee

et al. 2013

AAPS J

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Abstract. Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg −1 day −1 . Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31-to 0.48-fold (p<0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p<0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

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“…The GSP method has been successfully used to predict prognoses and is correlated with the severity of liver disease, chronic hepatitis, cirrhosis, hepatocellular carcinoma, and nonalcoholic fatty liver disease (19)(20)(21)(22)(23). The FDA has recommended the GSP method in its industry pharmacokinetics guidelines for patients with impaired hepatic function.…”

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confidence: 99%

A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

Shih

Pai

Yang

et al. 2013

Antimicrob Agents Chemother

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cRelatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA-and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P < 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P < 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.

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The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone—a novel galactose single‐point method as a measure of residual liver function

Cited by 8 publications

References 23 publications

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide

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