Tobramycin과 Gentamicin이 신장기능에 미치는 영향

Abstract

[한글]

체중 150∼200g의 웅성 백서 50마리를 saline투여군(대조군), gentamicin 100mg/kg·day군, tobramycin 100mg/kg·day군 및 tobramycin 200mg/kg·day군등 4군으로 구분해서 이들 항생제가 신장기능에 미치는 영향을 생체내 및 생체외 실험을 통해서 연구하였다.

각 군의 동물에 규정량의 약물 또는 saline을 13일간 매일 피하 주사하면서 요량, 요 삼투질농도 및 요중 용질 배설량을 측정하였으며, 적절한 간격으로 동물을 희생하여 신피질 조직의 능동적 유기산 운반능, 산소소모량 및 Na-K-ATPase활성도를 조사하여 다음과 같은 성적을 얻었다.

전 투여군에서 실험기간중 혈장내 creatinine농도(P^^cr) 및 creatinine제거율(C^^cr) 즉, 사구체여과율은 변화를 보이지 않았으나 gentamicin 및 tobramycin고농도군에서 aminoglycoside nephrotoxicity의 전형적인 양상인 다뇨증 및 요 삼투질 농도의 감소현상이 현저히 나타났으며 이런 변화는 동량을 투여했을 경우 tobramycin에 비해 gentamicin이 심했다. 약물투여 1주일경부터 negative free water clearance(T**c^^H2O)는 오히려 증가하는 경향을 보였는데 이는 Henle씨 고리에서의 능동적 Na이동 및 원위 nephron에서의 항이뇨호르몬(antidiuretic hormone, ADH)에 의한 수분 재흡수에 이상이 초래되지 않았음을 나타낸다. 약물에 의해 유발된 요량 증가시 Na**+ 배설이 증가되는 점으로 미루어 natriuresis에 의한 삼투성 이뇨에 의해서 다뇨증이 발생함을 알 수 있었다.

Gentamicin 및 tobramrcin고농도군에서 신피질 절편의 유기산 이동능이 현저하게 감소되었으나 유기산과 운반체(carrier)간의 친화력(Km)은 뚜렷한 변화가 없었다. 이는 이들 항생제에 의해서 운반체의 생화학적 성상은 변화를 받지 않고 정상적인 근위세뇨관 세포막 면적이 감소되어 조직 단위 중량당 운반체 수가 감소되기 때문인 것으로 풀이된다.

약물투여후 신피질 절편의 산소소모량이 감소되었으며 그 감소 절도는 gentamicin 및 tobramycin고농도군에서 현저하므로 이들 약물에 의해 활성적인 근위세뇨관 막 면적이 감소됨을 됫받침하였다.

약물투여후 신피질 microsome의 Na-K-ATPase활성도에 대한 실험결과 Vmax가 증가한 반면 Km은 변화가 없어서 단위 막 면적당 Na**+펌프의 수가 중가함을 알 수 있었다.

이상의 결과를 종합하면 aminoglycoside에 의해 야기된 다뇨중 및 요 농축도의 감소는 근위세뇨관에서 Na**+ rejection곁과 초래되는 삼투성 이뇨현상이며 gentamicin 및 tobrarmycin에 의한 신장기능의 장애기전은 상호 유사하나 그 정도는 tobramycin에 비해서 gen

tamicin이 심한 것으로 사료된다.

[영문]

Changes in renal functions of rats injected with gentamicin or tobramycin were studied in vivo anti in vitro.

50 male rats (betray weight 150∼200 g) of mixed breed were divides into four groups: saline(control), gentamicin(100 mg/kg·day), low dose tobramycin(100 mg/kg·day) and high dose tobramycin(200 mg/kg·day) groups. Animals in each group were injected daily with saline or one of the two drugs for 13 days. Some of the animals in each group were sacrificed in an appropriate interval to obtain blood samples and for in vitro analysis of renal functions. In the remaining animals, daily measurements were made of urine volume, urine osmolality and urine solute excretion.

In all four groups, the plasma creatinine concentration(P^^cr) did not change during the 13 days of drug treatment.

In clearance studios, the glomerular filtration rate(estimated by the endogenous creatinine clearance, C^^cr) did not decrease during the treatment period. However, gentamicin-and high dose tobramycin-injected rats demonstrated the typical pattern of aminoglycoside nephrotoxicity characterized by polyuria and low urine osmolality. These changes were more pronounced in rats receiving gentamicin than in rats receiving tobramycin at the same dose. Despite the reduction in urine osmolality and polyuria, the negative free water clearance(T**c^^H2O) did not

decrease below the control level during the first week of drug injection, after

that it increased slightly suggesting that both active Na**+ transport along the

Henle's loop and ADH-induced water reabsorption in the distal nephron were not

impaired by the drugs.

The increase in urine output in gentamicin- and in high dose tobramycin-injected

rats was associated with an increase in solute excretion, supporting the notion

that the aminoglycoside-induced polyuria is due to osmotic diuresis. Analysis of

solute excretions indicated that the nature of the osmotic diuresis was

natriuresis.

In in vitro studies carried out on renal cortical slices, steady-state

distribution of phenolsul-fonphthalein(PSP) between renal cortical slicers and

incubation medium (i.e., PSP S/M ratio) appealed to be significantly reduced by

drug treatments, espicially in rats injected with gentamicin at 100 mg/kg·day and

tobramycin at 200 mg/kg·day. Kinetic analysis of PSP transport revealed that the

Vmax of PSP influx into tissue was significantly reduced but the Km and the efflux

rate constant were not appreciably altered in aminoglycoside-treated animals. These

indicate that the impairment of renal cortical PSP accumulation was primarily

attributed to the reduction in carrier numbers per unit tissue mass. This in turn

suggests that the area of functional proximal tubular cell membrane is decreased

after chronic treatment of aminoglycoside antibiotics.

The rate of oxygen consumption peer unit mass of renal cortical slices, in vitro,

was markedly decreased in rats injected with gentamicin (100 mg/kg·day) and With

high dose tobramycin (200 mg/kg·day) for more than 4 days. This again suggests

that the mass or functional tissue in renal cortex is decreased after the

aminoglycoside treatment.

The activity of the Na-K-ATPase in renal cortical microsome was increased in rata

treated with gentamicin (100 mg/kg·day) or with tobramycin(100 or 200 mg/kg·day).

This increase of the enzyme activity was associated with an increase of the Vmax

but not with an altered Km, suggesting that the number of enzyme molecules (hence

the Na**+ pump) per unit area of basolateral membrane is actually increased in

aminoglycoside treated rats.

From these results, we conclude that 1) the aminoglycoside-induced polyuria and

renal concentrating defect fire due to osmotic diuresis induced by proximal Na**+

rejection as a consequence of the reduction in functional tissue mass in proximal

tubules, and 2) the mechanisms with which gentamicin and tobramycin impair renal

functions are basically identical but the nephrotoxic potential of gentamicin is

relatively higher than that of tobramycin.