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

Mephenytoin disposition and serum bile acids as indices of hepatic tinction 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’-hydroxymephenytoi metabolite in a 0- to S-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. (Clin Pharmacol Ther 1997;62:527-37.)

Patricia A. Arm, MD, Adedayo Adedoyin, PhD, Adrian M. DiBisceglie, MD, Jeanne G. Waggoner, MD, Jay H. Hoofnagle, MD, Grant R Wilkinson, PhD, and Robert A. Branch, MD Nashville, Tenn., Pittsburgh, Pa., and Bethesda, Md.

Chronic viral hepatitis ranges in severity from a mild form of liver dysfunction to frank hepatic failure. Impaired hepatocyte function is frequently present along with changes in vascular flow and

From the Vanderbilt University School of Medicine, Department of Pharmacology, Nashville; the Center for Clinical Pharma- cology, University of Pittsburgh Medical Center, and the De- partment of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh; and the National Institute of Digestive and Kidney Diseases, Liver Disease Section, National Institutes of Health, Bethesda.

Supported in part by U.S. Public Health Service grant GM31304. Received for publication Feb. 19, 1997; accepted July 24, 1997. Reprint requests: Robert A. Branch, MD, FRCP, Center for

Clinical Pharmacology, University of Pittsburgh Medical Cen- ter, 623 Scaife Hall, Pittsburgh, PA 15213.

13/l/85012

architecture resulting from shunts, especially in se- vere disease. Both are important parameters in the hepatic metabolic elimination of drugs and other xenobiotics, but unfortunately there is no simple test to assess their relative contributions or indicate the degree of hepatic metabolic dysfunction. Standard biochemical liver function tests are often of little value in this regard. Among the standard indicators that are used in the assessment of liver function are elevated serum concentrations of total conjugated primary bile acids that results from reduced clearance. They are generally accepted to be sensitive and moderately specific markers of liver disease, though conjugated cholic acid is more specific.lm3 They have been shown to reflect the histologic activity and severity of hepatitis4,’ and to predict mor- tality in patients with cirrhosis.6 In general, these

527

528 Arns et al. CLINICAL PHARMACOLOGY & THERAPEUTICS

NOVEMBER 1997

Table I. Viral causes of hepatitis in patients with chronic viral hepatitis

Group Group Group Cause I II III

Hepatitis 8 9 4 Non-A, non-B 3 5 5

hepatitis Hepatitis delta 0 0 1

tests can distinguish good or bad liver function, but they provide little indication of the underlying cause or mechanism of altered function.

A potential approach to the discrimination between impaired hepatocyte function and changes in flow is the measurement of the hepatic metabolism of a highly extracted exogenous compound after oral administration7 In this situation, the extent of oral clearance and metabolism are dependent on hepatocyte function, whereas the magnitude of the first-pass effect is determined not only by this factor but also by the degree of portosystemic shunting.8 The pharmacokinetic characteristics of racemic mephenytoin suggest its potential as a probe to identify and quantify the independent contributions of impaired hepatocyte function and portosystemic shunting in liver disease.

S-Mephenytoin is rapidly and extensively metabolized by the liver to its 4’-hydroxylated metabolite (4’-hydroxymephenytoin) and exhibits a very high first-pass extraction after oral administration. This reaction is catalyzed by a polymorphic enzyme, with 97% of white subjects being extensive metabolizers and the remainder, with a genetically determined deficiency in this pathway, constituting poor metabolizers.’ By contrast, R-mephenytoin undergoes nonpolymorphic slow N-demethylation, and oral availability is essentially complete. Importantly, the stereoselective difference in disposition and oral availability is reflected by the R/S ratio of the two enantiomers in urine, with a ratio close to unity in poor metabolizers and greater than 1 in extensive metabolizers.” In extensive metabolizers, portosystemic shunting can reduce this ratio as a result of escape from exposure to hepatic enzymes and increased bioavailability of S-mephenytoin. Altered hepatocyte function, on the other hand, should reduce this ratio and also the total urinary excretion of 4’-hydromephenytoin caused by reduced metabo-

lism. Thus, in principle, the combination of these measurements should allow identification of changes in hepatocyte function and portosystemic shunting caused by liver disease.

The purpose of this study was to test this hypoth- esis by comparing the disposition of racemic mephenytoin in patients with chronic viral hepatitis with different degrees of disease severity to the disposition in healthy extensive metabolizer subjects. The study evaluated whether mephenytoin disposition could be used in the assessment of severity of liver disease and the independent contributions of impaired hepatocyte function and portosystemic shunting and compared the results to the more conventional measurements of histopathology and serum bile acids (cholylglycine).

METHODS The study was conducted in 35 patients from 21 to

63 years old with chronic hepatitis as a result of hepatitis B virus, hepatitis C virus, or hepatitis delta virus infection (Table I). The patients were studied during evaluation for, but before, entry into clinical trials of antiviral therapy conducted at the Clinical Center of the National Institutes of Health.‘r,i* None of the patients had any clinical evidence of gastrointestinal disorder(s) or a history of recent surgery, and none was taking drugs known to affect bile acid or mephenytoin metabolism (antiviral therapy was started after completion of the study). Per- cutaneous liver biopsy was performed within 4 weeks of the study. Two observers, to whom the mephenytoin and bile acid data were unknown, characterized the histopathology of the biopsy samples using standard criteria into the following cate- gories: chronic persistent hepatitis, chronic active hepatitis, or cirrhosis. For comparison, a cohort of 153 healthy individuals from 18 to 50 years old, who were not receiving any medication and who had no evidence of renal or hepatic dysfunction, were studied at Vanderbilt University. The separate studies were approved by the respective institutional review boards and written informed consent was obtained from each participant.

Each individual received a single 100 mg (460 p,mol) oral dose of racemic mephenytoin (Mesan- toin, Sandoz) after an overnight fast, All urine over the subsequent 8 hours was collected and an aliquot frozen (-20” C) until analysis. The urinary R/S ratio was determined by stereospecific capil- lary gas chromatography with use of a modified extraction procedure to that previously de-

CLIih7CAL PHARMACOI.OGY Kr THERN’EVTICS VOI.UME 62. h’CMKER 5 Ams et al. 529

Table II. Definition of patient groups based on the urinary recovery of 4’-hydroxymephenytoin and urinary R/S enantiomeric ratio of mephenytoin in an g-hour urine sample after single oral administration of 100 mg racemic mephenytoin, with values from 153 healthy subjects used as reference

--__ 4’-Hydroxymephenytoin Mephenytoin No. of patients

(wnoll8 hr) R/S ratio with hepatitis

Group I: good hepatic function without portosystemic shunt

Group II: good hepatic function with portosystemic shunt

Group III: poor hepatic function with or without portosystemic shunt

scribed.13 In brief, urine (1.5 ml) was acidified with an equal volume of 0.01 mol/L acetic acid and the mixture was placed on a 3 ml Chem Elut column (Analytichem International, Harbor City, Calif.). The column was then eluted with 6 ml methylene chloride and the eluate was evaporated to dryness under nitrogen. After reconstitution with 10 ~1 ethyl acetate, an aliquot was injected on the column of the gas chromatograph. A similar solid- phase extraction procedure was used in the determi- nation of 4’-hydroxymephenytoin. After incubation of 0.5 ml urine, containing 2.5 kg phensuximide as inter- nal standard, with 12N hydrochloric acid (1 ml) at 100” C for 1 hour, the cooled mixture was placed on a 3 ml Chem Elut column. After elution with 5 ml methylene chloride, the eluate was evaporated to dryness and the residue then dissolved in 40% meth- anol before HPLC analysis as described previously.‘” Serum samples were collected while the patient was fasting for estimation of cholylglycine concentrations with use of a commercially available radioimmunoas- say (CG-RIA, Abbott Laboratories, North Chicago, Ill.).

The patients with liver disease were subclassified according to their urinary dispositional characteristics of mephenytoin, relative to those of the control subjects. A 0- to g-hour urinary 4’- hydroxymephenytoin recovery within two standard deviations of the mean value of the control group was interpreted as indicative of normal hepatocellular function, whereas a value below this range, suggesting reduced metabolism, was interpreted as reflecting hepatocellular impairment. Because the 0- to g-hour urinary R/S ratio was not normally distributed, the control population was analyzed according to percentiles. In the patients with hepatitis, a value less than that of the 95th percentile of the control group, indicative of reduced first-pass extraction of S-mephenytoin, was considered to indi-

>82 >2.5 11

>82 c2.5 14

<82 c2.5 10

cate portosystemic shunting or impaired hepatic function. The combination of these criteria resulted in the subclassification of the 35 patients into three groups (Table II).

A one-way ANOVA was used for the parametric comparison of group means, whereas the Mann- Whitney U test was applied in the case of nonpara- metric analysis. The Duncan multiple range test was used for post hoc evaluations. The independence of the patient groups and the viral cause of hepatitis was examined by the x2 test.

RESULTS After administration of racemic mephenytoin, the

mean 4’-hydroxymephenytoin metabolite excretion (133 +- 90 versus 160 2 38 pmol; p < 0.005; Fig. 1) and the mean R/S enantiomeric ratio of unchanged mephenytoin (2.3 t 1.9 versus 14.5 + 18.9; p < 0.0001; Fig. 2) were significantly lower in patients with liver disease than in the control subjects. This was in spite of a significant degree of overlap in the range of these measures, especially 4’- hydroxymephenytoin, between the patients and the healthy subjects when the patients were evaluated as a single group. The R/S ratio appeared to be a more sensitive indicator of hepatitis-induced metabolic liver dysfunction because there was a more clear-cut discrimination between the groups than the 4’- hydroxymephenytoin urinary excretion (Figs. 1 and 2). Combination of these two measures as indicators of the degree of hepatocyte dysfunction and extent of portosystemic shunts allowed the liver disease population to be divided into three groups: normal hepatic function without portosystemic shunt (group I), normal hepatic function with portosystemic shunt (group II), and poor hepatic function with or without portosystemic shunt (group III). On this basis, group I had 11 subjects, group II had 14 subjects, and group III had 10 subjects (Table II). The rela-

530 Arns et al. CLINICAL PHABMACOLOGY & THERAPEUTICS

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500

= al 400 \ 5

E - 300

C .- 0 2 200 2 0.

f 100 3 d-

0

0

CONTROL HEPATITIS r-l=153 n=35

Fig. 1. Urinary recovery of 4’-hydroxymephenytoin in g-hour urine after oral administration of 100 mg racemic mephenytoin in normal subjects and patients with chronic viral hepatitis. The hatched ureas show the mean values 2 SD. The difference between the groups is significant @ < 0.005).

tionship of this classification to the other independent and more conventional measures of hepatic function was examined.

Histopathologic examination enabled the classification of the patients with liver disease into three groups: chronic persistent hepatitis (six subjects), chronic active hepatitis (20 subjects), and cirrhosis (eight subjects). One subject had a biopsy performed later than 4 weeks after the time of the metabolic study and was excluded from this analysis. This grouping represents different grades of the same disease rather than different types of diseases; on the recommended semiquantitative grading scheme of chronic viral hepatitis with use of the most widely used histologic activity index, these groups will translate to scorings of about 1 to 3,4 to 8, and 9 to 12, respectively.14V’5 This last group (cirrhosis) may actually represent more of a staging than grading of the disease. Different degrees of

severity of liver disease are thus represented among the patient group.

The serum level of the bile acid cholylglycine was used to evaluate liver function in all patients. The different groups, characterized on the basis of histopathologic examination of the biopsy specimens, had different levels of fasting serum cholylglycine. The mean level was highest in the cirrhosis group (232 2 173 ug/dl), followed by the chronic active hepatitis group (88 + 76 kg/dl), and the chronic persistent hepatitis group had the lowest mean level (40 -+ 16 @dl), although there was overlap between the groups (Fig. 3).

A relationship was observed between the serum cholylglycine level and indices of mephenytoin metabolism (Fig. 4). The subjects who excreted the lowest amount of 4’-hydroxymephenytoin or who had a low R/S ratio were those who had the highest serum level of cholylglycine, giving correlation coef-

CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 62, NUMBER 5

100

.c 80 0

F

g 60

2 cn G 40

Arm et al. 53 1

OOOQ)

ooooco

CONTROL HEPATITIS n=l53 n=35

Fig. 2. R/S enantiomeric ratio of mephenytoin in O- to S-hour urine obtained after oral administration of 100 mg racemic mephenytoin in normal subjects and patients with chronic viral hepatitis. The hatched areas indicate the mean values t SD. The difference between the groups is significant (p < 0.0001).

ficients of r = -0.53 Cp < 0.005) and r = -0.37 (j < O.OS), respectively. There was increased variability in individual cholylglycine levels at the lower levels of mephenytoin metabolic function. These relationships suggest that both measures-cholylglycine serum level and mephenytoin metabolism indices-relate to and reflect the degree of hepatic dysfunction. The different patient groups as characterized by mephenytoin disposition (Table II) showed different mean serum cholylglycine levels, although there was some overlap between the groups (Fig. 5). In addition, the number of patients from these different groups represented in each grade of the disease, based on histologic evaluation, was also different and reflected the severity of the disease (Fig. 6).

DISCUSSION This study has taken advantage of and used the

unique stereoselective disposition of racemic me-

phenytoin9316917 that can indicate the extent of first- pass loss (through the early urinary R/S enantio- merit ratio of unchanged drug) and the overall hepatic metabolic clearance or intrinsic metabolic clearance (through the 4’-hydroxymephenytoin cumulative urinary excretion and R/S enantiomeric ratio)‘* to investigate the independent contributions of portosystemic shunting and altered hepatocellular function to changes in hepatic metabolic function caused by liver disease. These measures and approach were applied in a group of patients with liver disease with different degrees of hepatic dysfunction with use of information obtained from a large normal population as reference.

Measures of mephenytoin disposition were used to divide the patients with liver disease into three groups that represent degrees of hepatocyte dysfunction or changes in vascular architecture. An R/S ratio greater than unity and normal 4’-

532 Arns et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

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600 0

n-6 n=20 n=6

Fig. 3. Serum cholylglycine levels in patients with histopathologic evidence of chronic viral hepatitis. The bars and hatched areas indicate the mean values of the group t SD. The one patient in whom a biopsy was not performed within 1 month of the study was excluded from this analysis. The difference between groups is significant (p < 0.0005) by one-way ANOVA. CPH, Chronic persistent hepatitis; CAH, chronic active hepatitis; CIR, cirrhosis.

hydroxymephenytoin excretion represented a group with normal hepatocyte function with no portosystemic shunt. A reduced R/S ratio but normal 4’- hydroxymephenytoin excretion represented normal hepatocyte function with portosystemic shunts. This is because more of the absorbed drug goes directly into the systemic circulation without being exposed to metabolizing enzymes in the liver, thus increasing the apparent bioavailability of S-mephenytoin, and the R/S ratio is consequently reduced. How- ever, with good hepatocyte function, the absorbed drug is still rapidly metabolized, resulting in normal 4’-hydroxymephenytoin excretion over an &hour period, given a plasma half-life of about 1 hour. A reduced RJS ratio and reduced 4’- hydroxymephenytoin excretion represented poor hepatocyte function with or without portosystemic shunts. This is because both first-pass loss and metabolism after absorption are reduced with poor hepatocyte function, resulting in low R/S ratio and low 4’-hydroxymephenytoin urinary excretion. Con- sequently, by use of these two measures, the severity

and mechanism underlying hepatic metabolic dysfunction may be elucidated.

Compared with the serum bile acid (cholylglycine) levels, a conventional liver function test, both measures of mephenytoin disposition characteristics exhib- ited significant inverse relationships (Fig. 4). These relationships support the contention that disposition of mephenytoin can be an indicator or measure of hepatic dysfunction and its severity. With use of the urinary excretion of 4’-hydroxymephenytoin as a measure of metabolic efficiency, only one subject with a urinary recovery within two standard deviations of the mean for normal subjects had an elevated cholylgly- tine level, whereas only two subjects with urinary recovery of 4’-hydroxymephenytoin less than two standard deviations had normal fasting cholylglycine levels. When the serum levels of cholylglycine were compared between the different groups (I to III) as classified by mephenytoin disposition characteristics, it was shown that groups I and II had similar mean values and almost complete overlap in range, whereas group III was distinctly different both in the mean and range of

CLlNICAL PHARMACOLOGY & THERAPEUTICS VOLUME 62, NUMBER 5 Awns et al. 533

600 1 I

i

a i 500 I

I = $ 400

I

3 a j

100

600

100 200 300 400

Urinary 4-OH Mephenytoin (pmole/8hrI

2.0 4.0 8.0 8.0

Urinary R:S Mephenytoin ratio

Fig. 4. The relationship between fasting serum cholylglycine levels and urinary recovery of 4’-hydroxymephenytoin (top panel; r = 0.53, p < 0.005) or R/S enantiomeric ratio of mephenytoin (bottom panel; r = 0.37, p < 0.05) in patients with chronic viral hepatitis (circles, group I; triangles, group II; squares, group III). The broken line represents an apparent threshold in mephenytoin disposition parameter below which the cholylglycine level was more variable and showed a greater-than-proportional increase.

534 Arns et al. CLINICAL PHABMACOLOGY & THEBAPEUTICS

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600 0

Group I Group II n-11 n=14

Group Ill n-10

Fig. 5. Fasting serum cholylglycine levels in patients with chronic viral hepatitis defined on the basis of mephenytoin disposition as having good hepatic function without evidence of portosystemic shunting (group I), good hepatic function with evidence of portosystemic shunting (group II), or poor hepatic function with or without portosystemic shunting (group III). Definitions of groups I through III are provided in Table II. The bars and hatched areas

indicate the mean values of the group + SD. The difference among the group mean values is significant by ANOVA @ < O.OOOS), with group comparisons being significant for all the group pairs except group I versus group II.

levels (Fig. 5). Serum levels of bile acids have previously been shown to be elevated in patients with hepatic dysfunction in proportion to reductions in hepatic intrinsic clearance.19,*’ Thus classification based on these mephenytoin disposition characteristics is in agreement with a conventional liver function test. The fact that the relationships between mephenytoin disposition parameters and serum bile acids is not stronger than observed is probably related to what is known about conventional liver function tests not being good indicators of hepatic metabolic activity. The data also provide indication that there may be a threshold of mephenytoin disposition characteristic at which there is a substantial and greater than proportional increase in serum bile acid (Fig. 4). How- ever, there is insufficient information in this study

to fully evaluate this, and further studies will be required to fully elucidate this possible phenomenon.

With respect to classification based on histologic examination of the biopsy specimens, the disposition characteristics of mephenytoin were also different between the groups. The histologic classification can be considered to differentiate severity of disease involvement rather than separating different disease entities.i4 Patients with the mildest form of disease involvement, as defined by chronic persistent hepatitis, were mostly from group II but in- cluded one from group I; those with more extensive involvement (chronic active hepatitis) consisted of patients from groups I, II, and III; whereas those with extensive disease (cirrhosis) were mostly from group III but with a few from group II (Fig. 6). In other words, none of the patients with chronic per-

CLINICAL PHARMA COLOGY & THERAPEUTICS VOLUME 62, NUMBER 5

sistent hepatitis had reduced 4’-hydroxymephenytoin urinary excretion, three of 20 patients with chronic active hepatitis had reduced 4’-hydroxymephenytoin urinary excretion, whereas only one of eight with cirrhosis had normal 4’-hydroxymephenytoi urinary excretion. This shows that not only was the classification based on mephenytoin disposition in agreement with the biochemical test but it also follows the trend with the classification based on histologic examination of biopsy specimens. This needs to be further investigated.

The additional advantage that could be derived from using mephenytoin disposition characteristics compared with conventional biochemical tests and histologic examination is its potential to identify borderline patients. These are represented by group II of the mephenytoin classification scheme. All the tests were clearly able to distinguish patients with no significant dysfunction and those with significantly reduced function (groups I and III, respectively). However, those in group II were harder to detect because they had cholylglycine levels comparable to group I and because group II contained an almost equal number of patients with chronic persistent hepatitis and chronic active hepatitis from histologic examination. Thus neither of these tests was able to clearly distinguish them. The use of 4’- hydroxymephenytoin excretion alone also would not be able to clearly differentiate them because they have normal hepatocyte function and excretion of 4’-hydroxymephenytoin was comparable to control subjects. The use of the R/S ratio suggested a significant level of portosystemic shunt in spite of the apparent normal hepatocyte function. Unfortu- nately, no independent method for assessment of portosystemic shunting was used that could confirm the pharmacokinetic evidence, but the data suggest that this approach may have merit and warrant further evaluation.

One conceptual limitation of the methodologic approach proposed by this study is that approxi- mately 3% of the white population and up to 20% of the Oriental population have a genetic defect in their ability to hydroxylate S-mephenytoin.’ Such poor metabolizers would have pharmacokinetic characteristics similar to those defined by group III in this study. It is unlikely that the occurrence of such individuals have biased the present study, because this frequency of poor metabolizers is much lower in a healthy population (about 3%) than was found in this population of patients with hepatitis (10 of 35, or 29%). Moreover, all patients in group

Avns et al. 535

Ill- Chronic Persistent Hepatitis

hronic Cirrhosis ctive epatitis

Fig. 6. The number of patients with biopsy-proven evidence of chronic persistent hepatitis, chronic active hepatitis, and cirrhosis when defined by mephenytoin’s disposition parameters as having good function with no evidence of portosystemic shunting (group I), good function with evidence of portosystemic shunting (group II), or poor function with or without evidence of portosystemic shunting (group III). Definitions of groups I through III are provided in Table II. The one patient in whom a biopsy was not performed within 1 month of the study was excluded from this analysis.

III had significant liver disease. One method to prevent misinterpretation of a genetic, rather than an acquired, defect is to concomitantly administer a substrate for an alternative isozyme of cytochrome P450 of which the metabolism is known to be affected by liver disease. Such a substrate must not compete with, or alter, the disposition of mephenytoin. In addition, if there is a genetic defect in the metabolism of the second compound, it must be present in the population at such low frequency that the occurrence of a combined genetic defect with mephenytoin would be rare. In this situation, genetic poor metabolizers of mephenytoin would have normal metabolism of the second substrate, whereas individuals with the acquired defect of liver disease would have impaired metabolism of both compounds. One such alternative compound is antipyrine, whose metabolism has been shown to be affected by liver disease’r Combined testing with both drugs may be appropriate for future use in clinical quantification of hepatic dysfunction. Alternatively, the complication with the genetic defect may be easily resolved by genotyping for CYP2C19 mutants. With the identification of the major genetic defect responsible for this poor metabohzer statusz2 and the development and use of a genotyping test that identifies individuals with this genetic defect,23,24 it will be possible to differentiate pa-

536 Arm et al. CLINICAL PHARMACOLOGY &THERAPEUTICS

NOVEMBER 1997

tients with acquired defect resulting from liver disease who will lack this mutation and will be genotypic extensive metabolizers. Although this may mean additional tests, we believe it will be required in only a very small proportion of patients. This is because, even with reduced excretion of 4’-hydroxymephenytoin in some patients, the amount excreted was still more than would be expected from genetically poor metabolizers, which is usually less than 25 bmol.

In summary, these data suggest that by taking advantage of the unique disposition characteristics of mephenytoin enantiomers and combining two measures of its disposition characteristics-urinary R/S enantiomeric ratio and urinary excretion of 4’- hydroxymephenytoin-it is possible to identify and gain insight into the mechanisms that contribute to observed changes in hepatic metabolic dysfunction. Chronic viral hepatitis that has progressed to cirrhosis is associated with marked reductions in S-mephenytoin hydroxylation and reduced 4’- hydroxymephenytoin urinary excretion. In addition, a subpopulation of patients with preserved hepatic function but with pharmacokinetic evidence of portosystemic shunting can be identified by combination of this measure with the urinary R/S enantio- merit ratio. This approach may therefore provide a quantitative discriminant index of severity of chronic viral hepatitis disease and some indications of the underlying mechanism. Its potential for sequential evaluation of hepatic function to assess the natural history of the disease within individual patients and to provide useful information in longitudinal follow-up merit further investigation.

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

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