Skaggs SPPS, University of California, San Diego, CA, USA.
Headache. 2010 Feb;50(2):249-55. doi: 10.1111/j.1526-4610.2009.01568.x. Epub 2009 Nov 17.
The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T(max) = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life.
The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds.
Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T(max), 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs).
The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of C(max)). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC(0-10h) was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A.
There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.
皮下（s.c.）舒马曲坦的绝对生物利用度为 96-100%。6 毫克 s.c.舒马曲坦（即 T(max)约为 0.2 小时）后的血浆浓度衰减曲线包括一个大的分布分量。单胺氧化酶-A（MAO-A）的代谢导致约 40%的 s.c.剂量以无活性的吲哚乙酸形式出现在尿液中。产品标签表明，MAO-A 抑制剂（MAOI-A）的联合使用会使舒马曲坦的血浆浓度增加 2 倍，消除半衰期增加 40%。
本研究的目的是确定基于药代动力学，MAOI-A 治疗是否应该阻止使用 6 毫克 s.c.舒马曲坦。
汇总药代动力学数据取自文献和葛兰素史克（GSK）研究 C92-050。半衰期被转换为速率常数，然后用于一个简单的房室模型（仅需要 3 个同时的微分方程）。该模型的接受标准包括在给药后 T(max)、1、2 和 10 小时观察到的舒马曲坦的血浆浓度。以 36 秒的分辨率生成了一组 1000 次浓度测量值。然后用同时给予吗氯贝胺时观察到的消除常数对模型进行了干扰，生成了第二组浓度测量值。然后将这两组数据进行绘图、比较差异，并再次进行积分以获得和比较曲线下面积（AUCs）。
两组测量值之间的最大绝对差异为 t = 2.95 小时的 2.85 纳克/毫升。只有在 t = 5.96 小时后，两组之间才出现 2 倍的差异，此时 MAOI-A 存在时的浓度为 3.72 纳克/毫升（或<4%的 C(max)）。在 t = 10 小时时，两组的浓度均<1 纳克/毫升（即低于检测定量下限），在没有和存在 MAOI-A 时 AUC(0-10h)分别为 97.4 和 117 纳克·小时/毫升。
没有药代动力学依据阻止 MAOI-A 和皮下舒马曲坦的联合使用。6 毫克 s.c.舒马曲坦的分布相主导和吸收完全解释了 MAOI-A 对血浆舒马曲坦浓度的微小影响。重要的是，这些发现不应外推到舒马曲坦的其他给药途径。
