Metabolism of amylobarbitone in patients with chronic liver disease

Abstract

Summary A single dose of amylobarbitone (3·23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured. The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3·5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3·5 g/100 ml). The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system. The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant β(h−1) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0·01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0·001) and the mean serum water clearance (Ce ml/min) representing amylobarbitone elimination by metabolism was reduced. The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism. Both patient groups showed an increase in the first dispositional rate constant α(h−1) and in the clearance (Ct ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain. The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0·11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.

A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.

“…The cause for the decrease is unknown as it did not correlate with the total plasma protein, or albumin concentrations, or the severity of the liver disease as assessed by the biochemical parameters measured. This is in contrast to amylobarbitone whose binding is decreased in patients with a low serum albumin (Mawer, Miller & Turnburg, 1972 . Conversely, an increase in free drug from 5% to 30% allows more free drug to be available for distribution into tissues and is associated with a sixfold increase in the volume of distribution.…”

The effects of age and liver disease on the disposition and elimination of diazepam in adult man.

“…In two individuals with chronic active hepatitis who had received diazepam intravenously, the drug clearance was also depressed, 13.0 and 17.9 ml/min. After recovery from acute viral hepatitis, the diazepam half-life returned almost to normal values; No statistically significant correlation was noted between the diazepam ti (a) in patients with cirrhosis or hepatitis (and drug clearance in cirrhosis) and any of the standard liver function tests.…”

“…The major involvement of the liver in the above metabolism of diazepam (10, U) would suggest that hepatic dysfunction might alter the drug's disposition and elimination, as' reported for other extensively metabolized drugs (12)(13)(14)(15)(16)(17)(18)(19)(20). Such a finding would be contrary to the general clinical impression that diazepam is a safe therapeutic' agent and a sedative of choice in patients with liver disease, a concept based on the observations that there' is no prolongation of the sedative effect or abnormality in the electroencephalographic pattern in such individuals after the administration of a single dose of the drug (21).…”

“…The delay in return of diazepam's elimination to normal in all five patients with acute viral hepatitis, in whom recovery of the biochemical parameters had been achieved, also suggests that such tests do not adequately reflect the capacity of the liver to metabolize diazepam. Serum albumin concentration and/or the prothrombin index have been shown to be good indicators for the prolongation of ti (P) of antipyrine (12), amylobarbital (13), and phenylbutazone (16), but only when these functions showed major impairment. However, these findings are of little general predictive value, especially when these parameters are within the normal range but drug disposition and elimination are significantly altered: a classification into which many of our patients could be placed.…”

Impairment of cognitive function associated with hydroxyamylobarbitone accumulation in patients with renal insufficiency

“…Determination of serum amylobarbitone and hydroxywnylobarbitone Serum concentrations of amylobarbitone and hydroxyamylobarbitone were determined as described previously (Balasubramaniam, Mawer & Rodgers, 1969;Balasubramaniam, Lucas, Mawer & Simons, 1970;Mawer, Miller & Turnberg, 1972). An internal standard, quinalbarbitone in the case of amylobarbitone, and cyclobarbitone in the case of hydroxyamylobarbitone, was added to an aliquot of serum.…”