Clinical Pharmacokinetics

, Volume 9, Issue 6, pp 511–544 | Cite as

Clinical Pharmacokinetics of the Antituberculosis Drugs

  • Mack R. Holdiness
Review Articles

Summary

The quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable ‘first-pass’ effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid.

With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug’s antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide.

The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group. The elimination half-life of kanamycin increases from 107 minutes in younger individuals to 282 minutes in elderly populations.

Recent data indicate that isoniazid, rifampicin, ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin and cycloserine appear in measurable quantities in breast milk, with isoniazid having the highest recorded level of 2.3% of a daily administered dose.

Pharmacokinetic drug interactions and techniques for therapeutic drug monitoring of each of these agents (and some of their metabolites) are also briefly reviewed. Consideration of the pharmacokinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.

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© ADIS Press Limited 1984

Authors and Affiliations

  • Mack R. Holdiness
    • 1
  1. 1.Department of Pharmacology and Experimental TherapeuticsLouisiana State University Medical CenterNew OrleansUSA

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