Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease

Abstract

SUMMARY The possible existence of kinetic interactions between rifampicin and isoniazid and the effect of the concomitant presence of an impaired liver function were investigated in man.In a first study normal healthy subjects and patients with chronic liver disease received, on three different occasions, a single dose of 600 mg rifampicin or isoniazid and of rifampicin and isoniazid associated in randomized sequences. The results have shown that in both groups the serum levels, half-life values, and urinary excretion of each drug given alone are not significantly different from those observed when the other drug is associated. Serum levels and half-life of rifampicin and isoniazid were significantly higher in patients with chronically impaired liver.In a second study, rifampicin and isoniazid were given in combination at the same doses as in the first study over a period of one week. The results have shown a trend to decrease in the serum levels of rifampicin of the healthy subjects and a trend to increase in the patients with chronic liver disease on day 7 of treatment. In both groups a reduction in the half-life of rifampicin was also observed. No changes in serum isoniazid concentrations were observed between day 1 and day 7 in the healthy subjects, whereas a significant increase was observed in the patients. No significant changes in the half-life of isoniazid were observed.

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

“…There is a growing literature on the influence of liver disease on drug disposition, with prolongation in the TiA being reported for antipyrine (Branch et al, 1973), phenylbutazone (Levi, Sherlock & Walker, 1968), carbenicillin (Hoffman, Cestero & Bullock, 1970), chloramphenicol (Kunin, Glazko & Finland, 1959) and rifamycin (Acocella, Bonelloa, Garimoldi, Mainardi, Tocini & Nicolis, 1972) The high clearance of (+)-propranolol found in normal subjects, similar to those previously reported , correlated with and was numerically similar to the clearance of ICG. Although one drug is metabolized and the other actively transported to the bile, their hepatic extraction ratios must have been equally high so that the clearance values represented were a slight underestimate of liver blood flow.…”

Influence of liver disease on the elimination of drugs

“…The kinetics of INH and rifampicin were studied by Acocella et al (83) in 13 patients with liver disease. 100 mg INH and 300 mg rifampicin were administered orally after an overnight fast.…”

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

“…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).…”