Liver disease, pharmacokinetic

Yamada S, Yamamota T, Suou T, et al. Clinical significance of benzoate-metabolizing capacity in patients with chronic liver disease pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol 1992 76(1) 53-62. 

T. F. Blaschke, Protein binding and kinetics of drugs in liver disease, Clin. Pharmacokinet, 2, 32-44 (1977). 

AED pharmacokinetic data are summarized in Table 52-3. For populations known to have altered plasma protein binding, free rather than total serum concentrations should be measured if the AED is highly protein bound. Conditions altering AED protein binding include chronic renal failure, liver disease, hypoalbuminemia, burns, pregnancy, malnutrition, displac-... 

A decrease in the concentration of albumin (liver disease, nephrotic syndrome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumia... 

Pharmacokinetics in specific populations to demonstrate the effect of age and disease on kinetics, for example, young, elderly, patients with renal failure, liver disease, cardiac failure... 

Renai/Hepatic function impairment The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency only have been evaluated after single dose administration. In a single dose study of patients with anuric renal failure, the apparent clearance was approximately 40% lower and the elimination half-life was 1.6-fold greater than that in healthy controls. In a study of 14 people with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than that reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, exercise caution when patients with renal or hepatic insufficiency are treated with rimantadine. 

Pharmacokinetics Rapidly, completely absorbed from G1 tract rectal absorption variable. Widely distributed to most body tissues. Acetaminophen is metabolized in liver excreted in urine. Dichloralphenazone is hydrolyzed to active compounds chloral hydrate and antipyrine. Chloral hydrate is metabolized in the liver and erythrocytes to the active metabolite trichloroethanol, which maybe further metabolized to inactive metabolite. It is also metabolized in the liver and kidneys to inactive metabolites. The pharmacokinetics of isometheptene is not reported. Removed by hemodialysis. Half-life Acetaminophen 1-4 hr (half-life is increased in those with liver disease, elderly, neonates decreased in children). 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

The pharmacokinetics of lamivudine are described earlier in this chapter (see section, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV cell lines (17-19 hours) than in HIV-infected cell lines (10.5-15.5 hours) allows for lower doses and less ffeguent administration. Lamivudine can be safely administered to patients with decompensated liver disease. 

In patients with acute hepatitis and active hepatitis, protein binding of the glucocorticoids will be reduced and peak concentrations of administered glucocorticoids increased. Conversion of prednisone to prednisolone has been reported to be impaired in chronic active liver disease (409). However, although plasma prednisolone concentrations were more predictable after the administration of prednisolone than of prednisone to a group of healthy subjects (410), there was no difference in patients with chronic active hepatitis. There was also impaired elimination of prednisolone in these patients. In a review of the pharmacokinetics of prednisone and prednisolone it was concluded that fear of inadequate conversion of prednisone into prednisolone was not justified (411). Patients with hepatic disease suffer adrenal suppression more readily (111). 

Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet. 1999 37 399-431. 

Deres and co-workers (Bayer) [21] have reported a series of non-nucleosidic Biginelli-derived inhibitors 13, 14, 15 (Figure 11.2) of the hepatitis B virus (HBV). Chronic infection is a major cause of liver disease, and to date only interferon-a and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. The lead compound, Bay 41-4109 13 has a specific mechanism of action inhibiting capsid maturation and may be useful in combination therapies. In addition to efficacy in HBV transgenic mice [22], the compound possesses satisfactory pharmacokinetic and toxicology profiles. Efficacy in a clinical setting of HBV infection is under investigation. 

In the elderly there is a consistent increase in the maximum plasma concentration and the ti/2 of zolpidem. This is related to a reduced volume of distribution associated with a decrease in clearance [36], As with other hypnotics that are extensively degraded in the liver and show high protein binding, the pharmacokinetics of zolpidem is altered in patients with liver disease. Accordingly, in patients with hepatic insufficiency receiving zolpidem, the Cmax and the ti/2 are consistently increased [36, 37], In patients with renal insufficiency the disposition rate of zolpidem is decreased compared with that of age-matched healthy adults (Tab. 3). 

Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989 29 272-277. 

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