Abstract：
Acetazolamide (AZM) is a strong pharmacological sulphonamide-type (R-SO2-NH2, pKa 7.2) inhibitor of the activity of several carbonic anhydrase (CA) isoforms, notably of renal CA II (Ki, 12 nM) and CA IV (Ki, 74 nM). AZM is clinically used for about eighty years in various diseases including epilepsy and glaucoma. Pharmacological AZM increases temporarily the urinary excretion of bicarbonate (HCO3-) and sodium ions (Na+) and sustainably the urinary pH. AZM is excreted almost unchanged over several hours at high rates in the urine. Closely parallel concentrations of circulating and excretory AZM are observed upon administration of therapeutical doses of AZM. In a proof-of-principle study, we investigated the effects of the ingestion of a 250-mg AZM-containing tablet by a healthy volunteer on the urinary excretion of organic and inorganic substances over 5 h (range, 0, 0.5, 1, 1.5, 2, 3, 4, 5 h). Measured analytes included: AZM, amino acids and their metabolites such as guanidinoacetate, i.e. the precursor of creatine, of asymmetrically (ADMA) and symmetrically (SDMA) dimethylated arginine, nitrite (O = N-O-, pKa 3.4) and nitrate (O2N-O-, pKa -1.37), the major metabolites of nitric oxide (NO), the C-H acidic malondialdehyde (MDA; (CHO)2CH2, pKa 4.5), and creatinine for correction of analytes excretion. All analytes were measured by validated isotopologues using gas chromatography-mass spectrometry (GC-MS) methods. AZM excretion in the urine reached its maximum value after 2 h and was fairly stable for the next 3 h. Time series analysis by the ARIMA method was performed. AZM ingestion increased temporarily the urinary excretion of the amino acids Leu + Ile, nitrite and nitrate, decreased temporarily the urinary excretion of other amino acids. AZM decreased sustainably the urinary excretion of MDA, a biomarker of oxidative stress (i.e. lipid peroxidation). Whether this decrease is due to inhibition of the excretion of MDA or attenuation of oxidative stress by AZM is unknown. The acute and chronic effects of AZM on the urinary excretion of electrolytes and physiological substances reported in the literature are discussed in depth in the light of its extraordinary pharmacokinetics and pharmacodynamics. Tolerance development/drug resistance to AZM in chronic use and potential mechanisms are also addressed.
摘要：
乙酰唑胺（AZM）是一种强大的药理学磺酰胺型（R-SO2-NH2，pKa7.2）抑制剂，可抑制几种碳酸酐酶（CA）亚型的活性，特别是肾CAII(Ki，12nM）和CAIV（Ki，74nM)。AZM在临床上用于包括癫痫和青光眼的各种疾病约80年。药理学AZM暂时增加碳酸氢盐（HCO3-）和钠离子（Na）的尿排泄，并持续增加尿pH。AZM在尿液中以高速率在数小时内几乎不变地排出。在施用治疗剂量的AZM后,观察到循环和排泄AZM的浓度接近平行。在一项原理证明研究中，我们调查了健康志愿者摄入250毫克含AZM的片剂对5小时内有机和无机物质尿排泄的影响（范围，0、0.5、1、1.5、2、3、4、5h)。测量的分析物包括：AZM，氨基酸及其代谢产物，如胍基乙酸盐，即肌酸的前体，不对称（ADMA）和对称（SDMA）二甲基化精氨酸，亚硝酸盐（O=N-O-，pKa3.4）和硝酸盐（O2N-O-，pKa-1.37),一氧化氮（NO）的主要代谢产物，C-H酸性丙二醛（MDA；（CHO）2CH2，pKa4.5），和肌酐用于校正分析物的排泄。使用气相色谱-质谱（GC-MS）方法通过验证的同位素来测量所有分析物。尿液中的AZM排泄在2小时后达到最大值，并且在接下来的3小时内相当稳定。通过ARIMA方法进行时间序列分析。摄入AZM暂时增加了氨基酸Leu+Ile的尿排泄，亚硝酸盐和硝酸盐，暂时减少其他氨基酸的尿排泄。AZM持续降低尿中MDA的排泄，氧化应激（即脂质过氧化）的生物标志物。这种减少是由于抑制MDA的排泄还是由于AZM对氧化应激的减弱所致，目前尚不清楚。根据其非凡的药代动力学和药效学，深入讨论了AZM对文献中报道的电解质和生理物质尿液排泄的急性和慢性影响。还讨论了长期使用中对AZM的耐受性发展/耐药性和潜在机制。
