性别差异对药代动力学的影响可预测女性的药物不良反应。
Sex differences in pharmacokinetics predict adverse drug reactions in women.
机构信息
Department of Psychology, University of California, Berkeley, 2121 Berkeley Way West, Berkeley, CA, 94720, USA.
Department of Integrative Biology, University of California, Berkeley, 3040 VLSB, Berkeley, CA, 94720, USA.
出版信息
Biol Sex Differ. 2020 Jun 5;11(1):32. doi: 10.1186/s13293-020-00308-5.
BACKGROUND
Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs.
METHODS
Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased.
RESULTS
For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs CONCLUSIONS: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.
背景
女性出现药物不良反应（ADR）的频率几乎是男性的两倍，但性别作为产生 ADR 的生物学因素的作用仍知之甚少。目前大多数使用的药物都是基于对男性进行的临床试验批准的，因此女性可能会过度用药。我们确定药物药代动力学（PK）的性别差异是否预测 ADR 的性别差异。
方法
通过 ISI Web of Science 和 PubMed 数据库的组合，使用术语“药物、性别或性别、药代动力学、药效动力学、药物安全性、药物剂量和药物不良反应”进行了搜索，得到了 5000 多篇文章，其中有很多重叠。我们从每篇相关文章中获取了 PK 指标（主要是曲线下面积、峰/最大浓度和清除/消除率）的显著性别差异信息。从每篇相关文章中识别出 ADR，并将其分类为女性偏倚、男性偏倚或无性别偏倚。
结果
对于大多数经 FDA 批准的检查药物，女性表现出较高的血药浓度和较长的消除时间，这些 PK 与 ADR 的性别差异密切相关。在所评估的 86 种药物中，有 76 种药物的 PK 值在女性中更高；对于 59 种具有临床可识别 ADR 的药物，具有性别偏倚 PK 的药物中有 88%的情况下，性别偏倚 PK 预测了性别偏倚 ADR 的方向。96%的女性偏倚 PK 值的药物与女性 ADR 发生率高于男性的药物相关，但只有 29%的男性偏倚 PK 值预测了男性偏倚 ADR。只有一小部分药物的 PK 信息可以获得。
结论
药代动力学的性别差异强烈预测女性特有的 ADR，但对男性则不然。这种性别差异不能用体重的性别差异来解释。数百种药物的公共记录中缺乏性别分层 PK 信息，这让人担心 PK 值的性别差异普遍存在且具有临床意义。向女性和男性开相同剂量药物的常见做法忽略了药代动力学的性别差异和体重的二态性，增加了女性过度用药的风险，并导致了女性偏倚的药物不良反应。我们建议根据证据进行女性剂量减少，以对抗这种性别偏见。
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