The Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ther Drug Monit. 2011 Feb;33(1):115-9. doi: 10.1097/FTD.0b013e3181ff8bc5.
Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied.
To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population.
Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight.
The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%.
There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.
地美孕安（Diclectin）由 10 毫克琥珀酸多西拉敏（DOX）和 10 毫克盐酸吡哆醇组成，是加拿大治疗妊娠恶心和呕吐的首选药物组合。然而，其在女性中的起效时间和作用持续时间存在很大差异。为了了解和提高其有效性，必须研究这种琥珀酸多西拉敏/盐酸吡哆醇组合中成分的药代动力学的变异性。
确定以地美孕安（Diclectin）的形式口服两剂这种药物组合后 DOX 和吡哆醇的药代动力学，并通过与另一人群的静脉内给药比较计算其各自的相对生物利用度。
18 名年龄在 18 至 45 岁之间的非妊娠、非哺乳期健康女性空腹服用两剂地美孕安（Diclectin），并用 240 毫升水送服。使用串联质谱法分析 DOX 和吡哆醇及其四种活性代谢物：吡哆醛、吡哆醛-5'-磷酸（PLP）、吡哆胺和吡哆胺-5'-磷酸的血样。为了本研究的目的，DOX 和 PLP 的药代动力学值根据体重进行了调整。
计算 DOX-AUC0→∞ 的平均值为 3137.22 ± 633.57 ng·hr/mL（范围，2056.59-4376.06 ng·hr/mL）。计算 PLP-AUC0→∞ 的平均值为 5513.10 ± 2362.35 ng·hr/mL（范围，1572.56-10153.77 ng·hr/mL）。根据静脉内给药后 PLP-AUC0→∞ 的文献值和当前研究的数据，计算出地美孕安中吡哆醇的相对生物利用度为 100%。
口服 20 毫克地美孕安后，DOX-AUC0→∞ 的变异性为 2.1 倍，PLP-AUC0→∞ 的变异性为 6.5 倍。使用文献值和当前研究的数据，我们估计吡哆醇的口服生物利用度为 100%。因此，代谢而非生物利用度的个体差异可能是剂量指南中需要解决的重要变异性来源。
