Fechner J, Schwilden H, Schüttler J
Klinik für Anästhesiologie, Universität Erlangen-Nürnberg, Krankenhausstrasse. 12, 91054, Erlangen, Germany.
Handb Exp Pharmacol. 2008(182):253-66. doi: 10.1007/978-3-540-74806-9_12.
Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofol(G). The liberated propofol(G) compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater V(c), V(dss), significantly shorter alpha- and beta-half-life and a longer MRT (mean residence time) for propofol(G). The pharmacodynamic potency of propofol(G) appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation.
丙泊酚（2,6 - 二异丙基苯酚）在水中溶解度不足，因此被制成脂质乳剂。当丙泊酚用于提供全静脉麻醉或特别是在长期镇静期间，这可能存在缺点。人们对开发新的丙泊酚制剂或丙泊酚前体药物一直相当感兴趣。GPI 15715或磷丙泊酚（Aquavan注射剂；吉尔福德制药公司，马里兰州巴尔的摩）是第一种在人类志愿者和患者中进行了充分研究的水溶性前体药物。GPI 15751或磷丙泊酚被碱性磷酸酶裂解为磷酸盐、甲醛和丙泊酚。甲醛迅速代谢为甲酸。尽管甲酸蓄积是甲醇摄入毒性的主要发病机制，但迄今为止，尚无因使用磷丙泊酚或其他磷酸酯前体药物（如磷苯妥英）而导致毒性的报告。磷苯妥英已于1996年成功推向市场用于治疗癫痫持续状态。主要副作用是快速静脉注射GPI 15715或磷丙泊酚后出现感觉异常，磷苯妥英也有类似描述。GPI 15715或磷丙泊酚的药代动力学可用一个联合药代动力学模型来描述，该模型有一个用于GPI 15715的双室子模型和一个用于丙泊酚（G）的三室子模型。与脂质剂型的丙泊酚相比，游离的丙泊酚（G）表现出意想不到的药代动力学和药效学差异。我们发现丙泊酚（G）的中央室容积（V(c)）、稳态分布容积（V(dss)）显著更大，α和β半衰期显著更短，平均驻留时间（MRT）更长。通过脑电图和催眠的临床体征测量，丙泊酚（G）的药效似乎高于丙泊酚。总之，GPI 15715或磷丙泊酚非常适合用于提供麻醉或清醒镇静。
