Acute Hepatitis

Acute hepatitis is an inflammatory condition of the liver that is caused by viruses or hepatotoxins. In acute viral hepatitis, inflammatory changes in the hepatocyte are generally mild and transient, although they can be chronic (chronic active hepatitis) and severe, resulting in cirrhosis or death. Blaschke and Williams and their colleagues (12-15) have conducted informative studies of the effects of acute viral hepatitis on drug disposition. These investigators used a longitudinal study design in which each of a small number of patients was studied initially during the time that they had acute viral hepatitis and subsequently after recovery (Table 7.1). The drugs that were administered included phenytoin (12), tolbutamide (13), warfarin (14), and lidocaine (15). The most consistent significant finding was that the plasma protein binding of both phenytoin and tolbu-tamide was reduced during acute hepatitis. For both drugs, this was partly attributed to drug displacement from protein binding sites by elevated bilirubin levels. As a result of these changes, the distribution volume of phenytoin increased slightly during hepatitis (see Chapter 3). Although no significant change was noted in the average values of either phenytoin CLh or CLint, CLint was reduced by approximately 50% in the two patients with the greatest evidence of hepatocellu-lar damage. On the other hand, the reduction in tolbu-tamide binding to plasma proteins had no observable effect on distribution volume or CLjnt but did result in an increase in CLh . No consistent changes were observed in warfarin kinetics during acute viral hepatitis. However, prothrombin time was prolonged to a greater extent than expected in two of the five patients, reflecting impaired synthesis of Factor VII. Lidocaine kinetics also were not altered consistently during acute viral hepatitis, although clearance decreased in four of the six patients who were studied.

In general, drug elimination during acute viral hepatitis is either normal or only moderately impaired. Observed changes tend to be variable and related to the extent of hepatocellular damage incurred. If the acute hepatitis resolves, drug disposition returns to normal. Drug elimination is likely to be impaired most significantly in patients who develop chronic hepatitis B virus-related liver disease, but even then only late in the evolution of this disease (16). This stands in marked contrast to the severity of

Principles of Clinical Pharmacology TABLE 7.1 Pharmacokinetics of Some Drugs during and after Acute Viral Hepatitis fu Vd CLH CLint

Principles of Clinical Pharmacology TABLE 7.1 Pharmacokinetics of Some Drugs during and after Acute Viral Hepatitis fu Vd CLH CLint

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