title: Pharmacokinetics of antituberculosis drugs after oral isolated and simultaneous administration in triple combination.
abstract: On the basis of a mathematical analysis of the time course of the drug distributed in the organism there were studied pharmacokinetics of antituberculosis drugs after an isolated oral administration of doses used in daily treatment of tuberculosis, in INH, RMP, EMB, PZA, ETA, CS and TZ, and after a simultaneous--single and repeated--administration of INH, RMP, EMB in a triple combination, after the usual daily doses and after increased intermittent doses administered twice weekly. At first there were determined, with the use of chemical methods, blood concentrations of the antituberculosis drugs studied and their excretion with urine in an unchanged form. The results were analyzed pharmacokinetically by means of a one- compartment model with absorption. By an iteration process, based on non-linear regression analysis, the following pharmacokinetic parameters were calculated: Vd, Ka, Ke, T0.5 abs, T0.5 el, Tmax, Cmax, Clp tot and AUC. Their comparison revealed the following facts: The microbiologically most effective antituberculosis drugs--INH and RMP--are comparable even from the point of view of pharmacokinetics on account of similar pharmacokinetic parameters; in comparison with them EMB has half the size of the AUC, characterizing the efficacy of the drug. In this parameter PTA exceeds more than twice ETA; CS and TZ have a low Ke as well as Clp tot and a high T0.5 el, which is indicative of an insufficient excretion of both drugs. Pharmacokinetic parameters of PZA confirm the possibility of using the dose of 25 mg/kg in the treatment of tuberculosis. A simultaneous administration of the triple drug combination under study influences pharmacokinetic parameters of all the three antituberculosis drugs--it significantly decreases Ka as well as Ke, increases T0.5 el, Tmax, Vd and in INH also Clp tot, but only after a repeated administration. An intermittent administration of the mentioned triple drug combination significantly increases the area under the curve AUC in all the three antituberculosis drugs. This explains the same efficacy of higher doses of antituberculosis drugs, administered twice weekly, in comparison with a daily administration of lower doses of the same combination. The pharmacokinetic process of orally administered antituberculosis drugs can be analyzed according to a one-compartment model of pharmacokinetics, although the kinetics of certain antituberculosis drugs probably proceed in the organism in a more complicated way.
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000378:metabolism*; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D007700:Kinetics; D008297:Male; D012293:Rifampin / Q000008:administration & dosage; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin