Sulfamethoxazole と Trimethoprimの研究 ラットにおける吸収, 分布, 排泄, 代謝に関する検討 : Sulfamethoxazoleについて

抄録

This report is based on the studies of pharmacokinetic studies of sulfamethoxazole (SMX) with particular reference to the effect of coexistence of trimethoprim (TMP).
Methods :
Each group of animals comprises 6 Sprague-Dawley strain male rats weighting approximately 200 g. SMX was given either 100 mg/kg alone or combined with TMP 20 mg/kg. Drugs were given orally as suspensions in 5% gum arabic in volume of 2 ml/100 g animal weight. Animals were sacrificed in 0.5, 1, 2, 4, 6, 16, 24 and 48 hours after drug administration by exsanguination from cervical vein. Each organ was immediately excised. Brain, lung, liver, kidney, spleen, fatty tissues and contents of the rectum were processed by 0.4 N HClO₄ to make a 10% homogenate. SMX present in the filtered supernatant was assessed for its concentration. The assay of SMX was made according to the method of BRATTON-MARSHALL. Glucuronide fractions of SMX were determined employing ethyl acetate extraction as described by KOECHLIN et al.
Results :
Plasma concentration : Table 1 demonstrates changes in plasma levels of SMX after oral administration of SMX alone or SMX with TMP. Figure 1 illustrates concentrations of free SMX. The acetyl form of SMX corresponded approximately to 8 % of the total SMX and this relation remained practically identical when TMP was given together. As shown in Figure 1, the absorption of SMX was rapid reaching peak levels in the first 4 hours followed by a gradual decrease. No significant changes of plasma SMX concentration were detected whether SMX was given alone or combined with TMP; if any, the rats of SMX absorption appeared to be slightly retarded when TMP was given together.
Intra-organ distribution : Table 2 and Figure 2 present concentrations of SMX at different hours after dosing in the brain, lung, liver, kidney, spleen, fatty tissues and feces. The peak values in these organs roughly coincided with the maximum plasma concentration 4 hours post-administration. SMX in the kidney, liver, spleen, lung, brain and fatty tissues, in the order of decreasing concentration, was present mostly as the free form and acetyl form accounted less than 10% of the total. The concentrations in rectal contents were relatively elevated particularly at 6 hours after administration. These concentrations did not differ significantly between the animals which were given SMX alone and those given the combination of SMX and TMP.
Urinary excretion : Data relative to urinary excretion of SMX after SMX alone and SMX with TMP are tabulated in Table 3. The administered SMX was found at 72-82 % to be excreted in the urine during the first 48 hours after administration. Most of the SMX was excreted in the first 24 hours. N⁴-acetylated SMX was major metabolite followed by free-SMX and glucuronide. The amount of SMX excreted was found to be slightly more when SMX was given with TMP than that when SMX was given alone. The effect of combined administration was also detectable in the quantity of free-SMX in the urine. The free-SMX in the urine was found to be larger in quantity when SMX was given together with TMP.