The Effect of Rifampicin on Norethisterone Pharmacokinetics

Europ. J. clin. PharmacoI. 15, t93-197 (1979)European Journal of Clinical Pharmacology © by Springer-Verlag 1979The Effect of Rifampicin on Norethisterone PharmacokineticsD. J. Back, A. M. Breckenridge, Francesca Crawford, M. MacIver, M. L'E. Orme, B. K. Park, P. H. Rowe, and Eileen Smith Department of Pharmacologyand Therapeutics, Universityof Liverpool, England Summary. The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450-600 mg/day). Rifampicin caused a significant reduction in the A. U. C. of a single dose of I mg norethisterone from 37.8 _ 13.1 to 21.9 _+ 5.9 ng/ml X h (p < 0.01). The plasma norethisterone half life (/3-phase) was also reduced from 6.2 _ 1.7 to 3.2 +_ 1.0 h (p < 0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/rnl. Rifampicin caused a significant increase in antipyrine clearance, 6/3-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there were no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A . U . C . during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin. Key words: norethisterone, rifampicin; enzyme induction, antipyrine, 6 beta-hydroxycortisol, gamma-glutamyltranspeptidase. steroids [2-9]. It has been shown [10] that rifampicin enhances the metabolic destruction of ethinyloestradiol in the livers of women receiving rifampicin as compared to controls. No information is available on the effect of the antibiotic rifampicin on the rate of elimination of the progestogenic component of oral contraceptives. We have thus studied the pharmacokinetics of norethisterone in a group of women being treated with rifampicin during and after stopping the rifampicin.Materials and MethodsPatientsWe have studied 9 female patients (aged 18-42) who were receiving treatment with rifampicin for tuberculosis. Clinical details are shown in Table 1. As shown all the patients were also receiving isoniazid and/or ethambutol. Patients K. P. and B. S. stopped rifampicin while continuing with the alternative therapy but the other women stopped all their antituberculous therapy at the same time. Five women were treated with rifampicin for one year and three (H.A., A. O'C., B.S.) for only 3 months. One woman was receiving long term contraceptive steroid therapy with Minovlar ® (containing I mg norethisterone acetate and 50~tg ethinyloestradiol). All patients gave their written informed consent to the studies which were approved by the local ethical committee. No patient was taking any other drug during the period of the study.In 19

71 Reimers and Jezek [1] reported that of 51 women with tuberculosis taking contraceptive steroids, 38 had increased intermenstrual or breakthrough bleeding, a sign of relative oestrogenic deftciency, when given rifampicin. Further, at least 14 pregnancies have now been reported in women taking rifampicin in conjunction with contraceptiveSingle Dose StudiesThe eight women not on contraceptive steroid therapy each took a single tablet of Minovlar ®, after 0031-6970/79/0015/0193/$01.00194 Table 1. Patients studied Patient H.A. G.B. I.C. J.N. A. O'C. K.P. A.S. B.S. C. D a Age 18 21 41 21 42 23 26 29 Organ involved with TB Lung Lung Lung Lung Lymph Nodes Lymph Nodes Lung Kidney LungD. J. Back et al.: The Effect of Rifampicinon NoretbisteronePharmacokineticsDaily Dose of Rifampicin (mg) 450 600 600 600 450 600 450 600 600Other drugs & Dose/day Isoniazid 300 mg Isoniazid 300 mg Ethambutol 600 mg Isoniazid 300 mg Isoniazid 350 mg Isoniazid 200 mg Ethambutol 600 mg Isoniazid 300 nag Isoniazid 300 mg Ethambutol 600 nag Pyrazinarnide2000 mg Isoniazid 300 mg Isoniazid 300 mga On long term therapy with oral contraceptivesteroidsan overnight fast, towards the end of rifampicin therapy and again one month after stopping rifampicin. Blood samples (10 ml) were taken via an indwelling catheter in an arm vein, prior to each dose of Minovlar ®, and at 1, 2, 3, 4, 6, 8, 11, 14 and 24 h after dosing. The blood was taken into heparinized containers, centrifuged at 2000 rpm for 10 min and the supernatant plasma was removed and stored at 20 ° C prior to analysis. Plasma norethisterone concentrations were measured by a radioimmunoassay developed in this laboratory [11]. The plasma norethisterone concentration versus time curve was analysed according to a two compartment open model [12] and the plasma half life was calculated from the terminal apparently mono-exponential phase by least square regression (/3-phase). The area under the plasma concentration versus time curve (A. U. C.) was calculated from 0 to 24 h by the trapezoidal rule [13]. The area from 24 h to infinity was always less than 5% of the area from zero to 24 h.-Indices of Enzyme Induction a. Change in Plasma Antipyrine Half Life. In seven patients a single dose of antipyrine (600 mg) was given by mouth during and one month after stopping rifampicin. Blood samples were taken at 3, 6, 9, 12 and 24 h on both occasions and the plasma was analysed for antipyrine by radioimmunoassay [14] with the following minor modifications. The extraction volume was reduced to 1.8 ml and after the addition of saturated ammonium sulphate, the amount of antipyrine bound to the antibody was measured directly by resuspending the ammonium sulphate precipitate in distilled water (400 ~tl) and counting the radioactivity in N . E . 260 (4.5 ml) (Nuclear Enterprises, Edinburgh, Scotland), in a liquid scintillation counter. The plasma half lives and plasma clearances of antipyrine were calculated as de …… 此处隐藏：12755字，全部文档内容请下载后查看。喜欢就下载吧 ……