Clinical Pharmacokinetics of Rifampicin

Abstract

After oral administration on an empty stomach, the absorption of rifampicin (rifampin) is rapid and practically complete.

With a single 600mg dose, peak serum concentrations of the order of 10μg/ml generally occur 2 hours after administration. The half-life of rifampicin for this dose level is of the order of 2.5 hours.

The amount of rifampicin extracted by the liver during its first passage through the hepatoportal system and transferred to bile is of relevance for the time course of distribution of the antibiotic in the blood compartment. With doses of the order of 300 to 450mg, the excretory capacity of the liver for the antibiotic is saturated. As a consequence, increasing the dose of antibiotic results in a more than proportional increase in serum concentrations.

On repeated administration, and most likely as a consequence of self-induced (autoinduction) metabolism, the rate of disappearance of rifampicin from the blood compartment increases in the early phase of treatment, the phenomenon affecting mainly the levels following the peak, with a consequent reduction in half-life.

Approximately 80% of rifampicin is transported in blood bound to plasma proteins, mainly albumin. Rifampicin is well distributed, although to a different degree, in the various tissues of the human body. Probably in the hepatocyte, rifampicin undergoes a process of desacelylation. The metabolic derivative, desacetylrifampicin, is more polar than the parent compound, and microbiologically active. This metabolite accounts for the majority of the antibacterial activity in the bile. Rifampicin is almost equally excreted in the bile and urine, the recovery in the 2 fluids being of the same order of magnitude.

Administration of rifampicin to newborn infants and children is followed by blood levels generally lower than those.found in adults for the same dose levels. In patients with impaired liver and kidney function the elimination of the antibiotic from the blood compartment is slower than in normal subjects. Rifampicin has been found to compete with bilirubin and other cholefil substances for biliary excretion, giving rise to transient and reversible increased bilirubin and BSP retention values.

A kinetic model study on the transfer constants between various body compartments has indicated that rifampicin is rapidly absorbed from the intestine and that the absorption rate increases with time. Rifampicin as such is transferred into urine at a rale 3 times higher than the rate of transfer into bile. Desacetylrifampicin, the more polar metabolic derivative of rifampicin, behaves in the opposite way since its rate of transfer into bile is 4 times higher than that into urine. The rate of biotransformation of rifampicin into desacetylrifampicin is of the same order of magnitude as that of biotransformation of the latter into a further metabolic derivative, which could be a glucuronide conjugate.

Administration of rifampicin to man is associated with proliferation of the smooth endoplasmic reticulum of the hepatocyte and with a state of induction of the drug metabolising enzyme system in the liver. As a result, drug metabolism interactions of clinical significance have been found between rifamipicin and drugs such as oral anticoagulants, oral contraceptives, oral sulphonylurea, hypoglycaemic agents, corticosteroids and digitoxin.