Kulo A, Van Calsteren K, van de Velde M, Mulabegovic N, Verbesselt R, de Hoon J N, Verhaeghe J, Allegaert K
Department of Pharmaceutical and Pharmacological Sciences and Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium.
Eur Rev Med Pharmacol Sci. 2014;18(5):599-604.
Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population.
PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed.
Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In non-pregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023). Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51).
Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.
由于年轻女性对乙酰氨基酚清除率存在广泛差异，故将已发表的数据与新收集的观察结果合并，以寻找该特定人群中对乙酰氨基酚药代动力学（PK）的协变量。
采用非房室线性处置模型对年轻女性静脉注射负荷剂量（2g对乙酰氨基酚）后的PK估计值和临床特征[怀孕、体重、口服避孕药（OC）暴露情况]进行合并分析，数据以中位数和范围表示。采用秩相关分析将清除率（l/h）与体重联系起来，采用Mann-Whitney U检验比较各亚组（怀孕、OC暴露）之间的清除率（l/h.m²）。最后，对所有女性和所有非怀孕女性的清除率（l/h）进行多元回归模型分析。
基于73次对乙酰氨基酚PK估计值，记录到清除率存在8倍差异（范围为7.1 - 62.2 l/h），部分原因是清除率（l/h）与体重之间存在相关性（r² = 0.36）。与未怀孕女性的观察结果相比，分娩时的清除率（l/h和l/h.m²）及分布容积（l）（n = 36）更高。在非怀孕女性中，服用OC的女性（n = 20）的对乙酰氨基酚清除率（l/h.m²）高于未服用OC的女性（n = 17）（p = 0.023）。体重（p = 0.0043）和怀孕（p = 0.02）是对乙酰氨基酚清除率（l/h）的独立变量（r = 0.56）。在非怀孕女性中，体重（p = 0.009）和OC暴露（p = 0.03）是独立变量（r = 0.51）。
体重、怀孕和OC导致年轻女性静脉注射对乙酰氨基酚的清除率更高。除了化合物的特定相关性外，这些发现还揭示了年轻女性药物代谢的协变量。
