Interaction between anticonvulsants and human placental carnitine transporter.
OBJECTIVE
To examine the inhibitory effect of anticonvulsants (AEDs) 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 (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined.


RESULTS
Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier.


CONCLUSIONS
Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.
Wu
Shu-Pei
SP
School of Pharmacy and Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan.
Shyu
Ming-Kwang
MK
Liou
Horng-Huei
HH
Gau
Churn-Shiouh
CS
Lin
Chun-Jung
CJ
D000085:Acetates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000588:Amines; D000621:Aminoisobutyric Acids / Q000378:metabolism; D000927:Anticonvulsants / Q000009:adverse effects* / Q000145:classification / Q000493:pharmacokinetics*; D002331:Carnitine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D046508:Culture Techniques; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077206:Gabapentin; D006801:Humans; D000077213:Lamotrigine; D008954:Models, Biological; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D027701:Organic Cation Transport Proteins; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010920:Placenta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000378:metabolism; D011257:Pregnancy Proteins / Q000378:metabolism; D000074058:Solute Carrier Family 22 Member 5; D000078308:Tiagabine; D000077236:Topiramate; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D020888:Vigabatrin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000621:Aminoisobutyric Acids; D000927:Anticonvulsants; D002352:Carrier Proteins; D003509:Cyclohexanecarboxylic Acids; D009557:Nipecotic Acids; D027701:Organic Cation Transport Proteins; D011257:Pregnancy Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D010672:Phenytoin; D000077206:Gabapentin; D020888:Vigabatrin; D002331:Carnitine; D000077213:Lamotrigine; D000078308:Tiagabine