Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6.

BACKGROUND AND OBJECTIVES: Drug metabolism is influenced by liver disease because of the central role that the liver plays in metabolic activities in the body. However, it is still unclear how activities of specific drug-metabolizing enzymes are influenced by the presence and severity of liver disease. As a consequence, alteration in metabolism of specific drugs cannot be easily predicted or appropriate dosage adjustment recommendations made. METHODS: The activities of cytochromes P450 (CYP) 2C19 and 2D6 were investigated in a group of patients with mild or moderate liver disease (n = 18) and a group of healthy control subjects (n = 10). The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours. RESULTS: The elimination of S-mephenytoin was severely reduced among patients with liver disease, resulting in a 79% decrease in plasma clearance for all patients combined. This reduction was related to the severity of disease, patients with moderate disease being affected more severely than patients with mild disease. Similar differences were observed in the urinary excretion of 4'-hydroxymephenytoin metabolite. By contrast, there was no effect on the disposition of R-mephenytoin or debrisoquin. CONCLUSION: These results show selectivity in the effect of liver disease on activities of specific metabolizing enzymes, CYP2C19 being more sensitive than CYP2D6. They suggest that recommendations for modification in drug dosage in the presence of liver disease should be based on knowledge of the particular enzyme involved in metabolism of the drug. The results emphasize the need for further studies of each specific drug-metabolizing enzyme in the presence of liver disease.

Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis.

BACKGROUND AND OBJECTIVES: The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly extracted compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt. METHODS: The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting. RESULTS: The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. CONCLUSION: This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms.

The disposition of dapsone in cirrhosis.

Acetylation and N-hydroxylation of dapsone were evaluated in drug-free, non-smoking, normal subjects and subjects with cirrhosis (n = 7 for each group) after oral administration of 100 mg dapsone. Acetylation was not correlated with oral dapsone clearance or reduced in cirrhosis (0.37 +/- 0.43 versus 0.52 +/- 0.32). Fractional metabolic clearance of dapsone to its hydroxylamine was associated with dapsone oral clearance (r = 0.96, p less than 0.001, n = 14). In patients with cirrhosis, liver disease was associated with a trend to reduction in oral clearance (22%) and metabolic clearance of dapsone (48%). Protein binding was minimally reduced by cirrhosis (73% +/- 1% versus 69% +/- 3% in patients with cirrhosis (p less than 0.02). The dapsone recovery ratio was validated as a phenotypic index of the metabolic clearance of dapsone (r = 0.74, p less than 0.05). In an extended comparison of 14 patients with cirrhosis to 70 control subjects, cirrhosis was associated with reductions of 28% in dapsone recovery ratio (p less than 0.001), and 37% in acetylation ratio (p less than 0.01). Neither dapsone recovery ratio nor acetylation ratio correlated with Pugh Score, conventional liver function tests, indocyanine green clearance, or phenotypic measures of S-mephenytoin hydroxylase or debrisoquin hydroxylase activity. We conclude that cirrhosis is associated with minor changes in dapsone disposition and that dosage modification is not required. In addition, there is evidence that cirrhosis has a selective influence on activity of individual isozymes of cytochrome P450.

Liver volume measurements and three-dimensional display from MR images.

A method was investigated for measuring the volumes of human livers in vivo from magnetic resonance images and subsequently displaying these livers in three dimensions. Volumetric image sets of phantoms, healthy volunteers, and patients with cirrhotic livers were processed. Two image-processing approaches were compared for accuracy of liver measurements, intrasubject and interobserver variation, and speed of processing. Results indicated that both processing methods had a high degree of volume-measuring accuracy (within 8%), the interobserver measurements had a high coefficient of correlation (r = .9994), the intrasubject measurements had a low coefficient of variation (1.8%), and one method was four to five times faster than the other. The faster and easier of the two image-processing approaches provided satisfactory results for measuring liver volumes, but the slower approach provided more realistic-looking three-dimensional images of the liver.

Effect of severe alcoholic liver disease on the disposition of methadone in maintenance patients.

We studied methadone disposition in 11 maintenance patients with alcoholic liver disease of such severity that liver biopsy was contraindicated. Nine methadone-maintained patients with recent alcohol abuse but minimal or no evidence of liver disease served as controls. Most kinetic indices, including the apparent oral clearance and area under the concentration-time curves, were similar in patients and controls. Although the apparent terminal half-life of methadone was longer (p = 0.04) in the patients with liver disease, the peak plasma methadone level was lower (p = 0.03). None of the patients had signs or symptoms of methadone overdosage or abstinence at the time of study. Six patients and one control had flattened plasma methadone concentration-time curves. We hypothesize that, in severe liver disease, damage to hepatic drug-metabolizing systems is offset by damage to the capacity of the liver to store and release unchanged methadone. The usual methadone maintenance dose may be continued in stable patients with severe alcoholic cirrhosis.

Reduced sympathetic nervous system responsivity associated with the relaxation response.

Sympathetic nervous system activity was assessed in experimental and control subjects who were exposed to graded orthostatic and isometric stress during monthly hospital visits. After the first session, the experimental subjects practiced a technique that elicited the relaxation response. Their concentrations of plasma norepinephrine during subsequent graded stresses were significantly higher. No such changes were noted in the control group. These results were than replicated in the control group in a crossover experiment. The groups did not differ in their heart rate and blood pressure responses. These observations are consistent with reduced norepinephrine end-organ responsivity after regular elicitation of the relaxation response.

Treatment of anxiety: a comparison of the usefulness of self-hypnosis and a meditational relaxation technique. An overview.

We have investigated prospectively the efficacy of two nonpharmacologic relaxation techniques in the therapy of anxiety. A simple, meditational relaxation technique (MT) that elicits the changes of decreased sympathetic nervous system activity was compared to a self-hypnosis technique (HT) in which relaxation, with or without altered perceptions, was suggested. 32 patients with anxiety neurosis were divided into 2 groups on the basis of their responsivity to hypnosis: moderate-high and low responsivity. The MT or HT was then randomly assigned separately to each member of the two responsivity groups. Thus, 4 treatment groups were studied: moderate-high responsivity MT; low responsivity MT; moderate-high responsivity HT; and low responsivity HT. The low responsivity HT group, by definition largely incapable of achieving the altered perceptions essential to hypnosis, was designed as the control group. Patients were instructed to practice the assigned technique daily for 8 weeks. Change in anxiety was determined by three types of evaluation: psychiatric assessment; physiologic testing; and self-assessment. There was essentially no difference between the two techniques in therapeutic efficacy according to these evaluations. Psychiatric assessment revealed overall improvement in 34% of the patients and the self-rating assessment indicated improvement in 63% of the population. Patients who had moderate-high hypnotic responsivity, independent of the technique used, significantly improved on psychiatric assessment (p = 0.05) and decreased average systolic blood pressure from 126.1 to 122.5 mm Hg over the 8-week period (p = 0.048). The responsivity scores at the higher end of the hypnotic responsivity spectrum were proportionately correlated to greater decreases in systolic blood pressure (p = 0.075) and to improvement by psychiatric assessment (p = 0.003). There was, however, no consistent relation between hypnotic responsivity and the other assessments made, such as diastolic blood pressure, oxygen consumption, heart rate and the self-rating questionnaires. The meditational and self-hypnosis techniques employed in this investigation are simple to use and effective in the therapy of anxiety.