行政院國家科學委員會專題研究計畫 成果報告
Car nitine tr anspor ter s 對懷孕期間藥物吸收及分佈的影響
計畫類別： 個別型計畫
計畫編號：
NSC91-2320-B-002-195-執行期間： 91 年 08 月 01 日至 92 年 07 月 31 日
執行單位： 國立臺灣大學醫學院臨床藥學研究所
計畫主持人： 林君榮
計畫參與人員： 吳書沛, 徐明洸, 劉宏輝
報告類型： 精簡報告
處理方式： 本計畫可公開查詢
中
華
民
國 92 年 10 月 2 日
計畫編號：91-2320-B-002-195-計畫名稱：Carnitine transporters 對懷孕期間藥物吸收及分佈的影響
報告類別：研究報告-精簡報告
Purpose. To examine the inhibitory effect of anticonvulsants on carnitine transport by
the human placental carnitine transporter.
Methods. Uptake of radiolabeled carnitine by human placental brush-border
membrane vesicles was measured in the absence and presence of tiagabine, vigabatrin,
gabapentin, topiramate, valproic acid, and phenytoin. The mechanism of the
inhibitory action of tiagabine was determined.
Results. Most of the anticonvulsants inhibited placental carnitine transport. Kinetic
analyses showed that tiagabine had the greatest inhibitory effect (IC50 190
µ
M) and
the order of inhibitory potency was tiagabine > phenytoin > gabapentin > valproic
acid > vigabatrin, topiramate > lamotrigine. Further studies showed that tiagabine
competitively inhibited carnitine uptake by the human placental carnitine transporter,
suggesting it may be a substrate for this carrier.
Inhibitor (µM) 10-2 10-1 100 101 102 103 104 105 106 107 % o f co n tr o l 0 20 40 60 80 100 120 140 Phenytoin Topiramate Valproic acid Tiagabine Vigabatrin Gabapentin
Figure. Dose-response study of carnitine uptake in the presence of tiagabine (0.5-1,000 µM), phenytoin (1-1,000 µM),
gabapentin (1-10,000 µM), valproic acid (0.2-40,000 µM), topiramate (0.1-5,000 µM), or vigabatrin (0.2-50,000 µM). The data
are presented as the mean±SE for 3-5 experiments, each in triplicate.
1/Carnitine (µM)-1 -0.15 -0.10 -0.05 0.00 0.05 0.10 0.15 1 /C a rn it in e u p ta ke ( fm o le /m g p ro te in /2 0 s) -1 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 Tiagabine (mM) -0.75 -0.50 -0.25 0.00 0.250.50 0.75 Slo p e o f Lin e we ave r-Bu rk P lo t 0.00 0.02 0.04 0.06 0.08 Carnitine(µM) 0 20 40 60 80 100 120 C a rn it in e u p ta k e ( fm o le /m g p ro te in /2 0 s ) 0 200 400 600 800 1000
Figure. Concentration-dependent carnitine uptake (0.05 µM to 100 µM) in the presence of tiagabine at a concentration of 0 mM
(filled circles), 0.15 mM (empty circles), or 0.5 mM (filled triangles). A. Nonlinear regression analysis of carnitine uptake. B.
Lineweaver-Burk plot analysis of carnitine uptake. In the insert, a value of about 193 µM was estimated for the inhibition
triplicate. Each plot was generated from the mean of the individually fitted
parameters.
Table. Inhibition of carnitine uptake by anticonvulsants and other compounds in BBMV
isolated from human placenta. The 20 sec uptake was initiated by mixing 60 µl of uptake
buffer containing 80 nM 3H-carnitine and inhibitors with 40 µl of vesicle suspension.
The data are presented as the mean±SD for at least three experiments in triplicate.
Inhibitors Relative uptake
(% control) IC50 (mM) 1 mM 0.1 mM Control Carnitine Tiagabine Phenytoin Gabapentin Valproic acid Topiramate Vigabatrin Lamotrigine 100 2.70±4.17 * 31.6±6.60 * 39.0±6.32 * 57.0±3.87 * 68.3±2.40 * 66.4±9.30 * 62.6±5.66 * ---100 32.0±11.0* 51.6±7.64* 75.1±2.39* 84.6±9.88* 85.3±2.90* 91.7±10.4 83.0±3.66* 94.5±12.7 ---0.19±0.05 0.40±0.09 1.60±0.83 7.70±3.69 9.91±2.61 10.0±2.84 ---*
Significantly different from the control uptake by Student’s t test (p<0.05)
