Pharmacology: Rifampicin: The oral administration of rifampicin produces peak plasma concentrations in 2-4 hrs. The t½ of rifampicin varies from 1.5-5 hrs and is increased in the presence of hepatic dysfunction; it may be decreased in patients receiving isoniazid concurrently who are slow inactivators of rifampicin. Up to 30% of a dose of rifampicin is excreted in the urine; less than half of this may be unaltered antibiotic. Adjustment of dosage is not necessary in patients with impaired renal function.
Isoniazid: Peak plasma concentrations of 3-5 mcg/mL develop 1-2 hrs after oral ingestion of usual doses. From 75-95% of a dose of isoniazid is excreted in the urine within 24 hrs, as metabolites. The main excretory products in man are the result of enzymatic acetylation (acetylisoniazid) and hydrolysis (isonicotinic acid). The rate of acetylation significantly alters the concentrations of rifampicin that are achieved in plasma and its t½ in the circulation. The t½ of rifampicin may be prolonged in the presence of hepatic insufficiency.
Ethambutol: After oral administration, 75-80% of ethambutol is absorbed from the gastrointestinal tract. A single dose of 15 mg/kg produces a plasma concentration of about 5 mcg/mL at 2-4 hrs. Ethambutol has a t½ of 3-4 hrs. Within 24 hrs, 2/3 of an ingested dose of ethambutol is excreted unchanged in the urine; up to 15% is excreted in the form of 2 metabolites, an aldehyde and a dicarboxylic acid derivative. Renal clearance of ethambutol is approximately 7 mL/min/kg and ethambutol is excreted by tubular secretion in addition to glomerular filtration.
Pyrazinamide: Pyrazinamide is well absorbed from the gastrointestinal tract and attains peak plasma concentrations within 2 hrs. Plasma concentrations generally range from 30-50 mcg/mL with doses of 20-25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid. It is approximately 10% bound to plasma proteins. The plasma t½ of pyrazinamide is 9-10 hrs in patients with normal renal and hepatic function. The t½ of pyrazinamide may be prolonged in patients with impaired renal or hepatic function. Within 24 hrs, approximately 70% of an oral dose of pyrazinamide is excreted in urine, mainly by glomerular filtration. About 4-14% of the dose is excreted as unchanged drug; the remainder is excreted as metabolites.