Pharmacokinetic study of isoniazid and rifampicin in healthy Korean volunteers

Background: Isoniazid(INH) and rifampicin(RFP) are potent antituberculous drugs which have made tuberculous disease become decreasing. In Korea, prescribed doses of INH and RFP have been different from those recommended by American Thoracic Society. In fact they were determined by clinical experience rather than by scientific basis. Even there has been few reports about pharmacokinetic parameters of INH and RFP in healthy Koreans. Method: Oral pharmacokinetics of INH were studied in 22 healthy native Koreans after administration of 300 mg and 400mg of INH to each same person successively at least 2 weeks apart. After an overnight fast, subjects received medication and blood samples were drawn at scheduled times over a 24-hour period. Urine collection was also done for 24 hours. Pharmacokinetics of RFP were studied in 20 subjects in a same fashion with 450mg and 600mg of RFP. Plasma and urinary concentrations of INH and RFP were determined by high performance liquid chromatography(HPLC). Results: Time to reach peak serum concentration (Tmax) of INH was 1.05 ± 0.34 hrs at 300mg dose and 0.98 ± 0.59 hrs at 400mg dose. Half-life was 2.49 ± 0.88 hrs and 2.80 ± 0.75hrs, respectively. They were not different significantly(p > 0.05). Peak serum concentration(Cmax) after administration of 400mg of INH was 7.14 ± 1.95mcg/mL which was significantly higher than Cmax (4.37 ± 1.28mcg/mL) by 300mg of INH(p < 0.01). Total clearance(CLtot) of INH at 300mg dose was 26.76 ± 11.80mL/hr. At 400mg dose it was 21.09 ± 8.31 mL/hr which was significantly lower(p < 0.01) than by 300mg dose. While renal clearance(CLr) was not different among two groups, nonrenal clearance(CLnr) at 400mg dose (18.18 ± 8.36mL/hr) was significantly lower than CLnr (23.71 ± 11.52mL/hr) by 300mg dose(p < 0.01). Tmax of RFP was 1.11 ± 0.41 hrs at 450mg dose and 1.15 ± 0.43 hrs at 600mg dose. Half-life was 4.20 ± 0.73 hrs and 4.95 ± 2.25 hrs, respectively. They were not different significantly(p > 0.05). Cmax after administration of 600mg of RFP was 13.61 ± 3.43mcg/mL which was significantly higher than Cmax(10.12 ± 2.25mcg/mL) by 450mg of RFP(p < 0.01). CLtot of RFP at 450mg dose was 7.60 ± 1.34mL/hr. At 600mg dose it was 7.05 ± 1.20mL/hr which was significantly lower(p < 0.05) than by 450mg dose. While CLr was not different among two groups, CLnr at 600 mg dose(5.36 ± 1.20mL/hr) was significantly lower than CLnr(6.19 ± 1.56mL/hr) by 450mg dose(p < 0.01). Conclusion: Considering Cmax and CLnr, 300mg, of INH and 450mg RFP might be sufficient doses for the treatment of tuberculosis in Koreans. But it remains to be clarified in the patients with tuberculosis.