Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid
European Journal of Clinical Pharmacology, Volume 63, No. 7, Year 2007
Notification
URL copied to clipboard!
Description
Objective: This study evaluated the pharmacokinetics of isoniazid (INH) associated with optimal early bactericidal activity (EBA), defined as 90% of the maximum EBA (EBA90) and the influence of N-acetyltransferase-2 (NAT2) subtype on the ability of pulmonary tuberculosis (PTB) patients to reach the identified pharmacokinetic values after INH doses ranging from 0.2 to 10-12 mg/kg body weight. Methods: INH serum concentrations and NAT2 subtype were determined during four studies of PTB patients in three of whom the EBA of INH was determined. The relationship of EBA to area under the curve (AUC) (AUC 0-∞) and 2-h serum concentrations was examined by exponential regression and fitted curves estimated the AUC0-∞ and 2-h serum concentrations at which EBA90 was reached. Results: EBA90 was reached at an AUC0-∞ of 10.52 μg/ml per hour and 2-h serum concentrations of 2.19 μg/ml. An AUC0-∞ of 10.52 μg/ml per hour was reached by all 66 patients receiving a 10-12 mg/kg INH dose and all 21 receiving 6 mg/kg, except 1 of 10 (10%) homozygous fast (FF) acetylators; however, at 5 mg/kg, 4 of 12 (33%) FF and 26 of 27 (96%) heterozygous fast (FS), but all 21 homozygous slow (SS) acetylators did so; and 1 of 3 (33%) FF, 2 of 6 (33%) FS, but all 4 SS acetylators at dose 3 mg/kg. An INH 2-h serum concentration of 2.19 μg/ml was reached by all 66 patients receiving 10-12 mg/kg and all 21 receiving 6 mg/kg, except for 2 (20%) FF acetylators at a dose of 5 mg/kg; however, only 3 (25%) of 12 FF acetylators, but 26 (96%) of 27 FS acetylators, and all 21 SS acetylators reached this concentration; and at a dose of 3 mg/kg, 1 (33%) of 3 FF acetylators, 2 (33%) of 6 FF, but all 4 SS acetylators. Conclusions: At a 6 mg/kg dose, all except a minority of FF NAT2 acetylators, achieve an INH AUC0-∞ and 2-h INH serum concentrations associated with EBA90, as did all 4 SS acetylators receiving 3 mg/kg. Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH. © 2007 Springer-Verlag.
Authors & Co-Authors
Donald, Peter Roderick
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
Parkin, Donald P.
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
Seifart, Heiner I.
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
Schaaf, Hendrik Simon
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
Van Helden, Paul D.
South Africa, Stellenbosch
Stellenbosch University
Werely, Cedric J.
South Africa, Stellenbosch
Stellenbosch University
Sirgel, Frederick Adriaan
South Africa, Stellenbosch
Stellenbosch University
Venter, Amour
South Africa, Stellenbosch
Stellenbosch University
Maritz, Johannes Stephanus
South Africa, Tygerberg
South African Medical Research Council
Statistics
Citations: 94
Authors: 9
Affiliations: 3
Identifiers
Doi:
10.1007/s00228-007-0305-5
Research Areas
Genetics And Genomics