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Involvement of Recognition and Interaction of Carnitine Transporter in the Decrease of l-Carnitine Concentration Induced by Pivalic Acid and Valproic Acid

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Abstract

Purpose

Prodrugs with pivalic acid and valproic acid decrease l-carnitine concentration in plasma and tissues by urinary excretion of acylcarnitine as pivaloylcarnitine (PC) and valproylcarnitine (VC), respectively. We investigated the role of the Na+/l-carnitine cotransporter in the porcine kidney epithelial cell line, LLC-PK1 for the decrease of l-carnitine concentration.

Methods

The uptake of l-[3H]carnitine, acetyl-l-[3H]carnitine (AC), l-[3H]PC and l-[3H]VC were investigated in LLC-PK1 cells seeded in a 6-well culture plate.

Results

l-Carnitine and AC uptake in LLC-PK1 cells exhibited Na+ dependency. The K m values for l-carnitine and AC uptake were 11.0 and 8.18 μM, respectively. These results indicated expression of Na+/l-carnitine cotransporter in LLC-PK1 cells. PC and VC inhibited Na+/l-carnitine cotransporter in the competitive (K i = 90.4 μM) and noncompetitive (K i = 41.6 μM) manners, respectively. PC and VC uptake by Na+/l-carnitine cotransporter were not observed in LLC-PK1 cells.

Conclusions

These data suggested that PC and VC formed in the body could not be reabsorbed in the kidney, resulting in the decrease of l-carnitine concentration. In addition, inhibition of l-carnitine reabsorption by VC with lower K i value could induce the decrease of l-carnitine concentration. Collectively, the recognition and interaction of Na+/l-carnitine cotransporter are important factors for carnitine homeostasis.

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Abbreviations

AC:

acetyl-l-carnitine

PC:

pivaloylcarnitine

VC:

valproylcarnitine

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Acknowledgments

We cordially thank Yoshihiko Katsuyama and Katsunori Sakai in Shionogi & Co., Ltd. for synthesizing the labeled and unlabeled compounds.

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Author notes

  1. Noboru Okamura

    Present address: Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

Authors and Affiliations

  1. Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan

    Noboru Okamura, Shuichi Ohnishi, Hiroyuki Shimaoka, Ryo Norikura & Hiroshi Hasegawa

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  1. Noboru Okamura
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  2. Shuichi Ohnishi
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Correspondence to Shuichi Ohnishi.

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Okamura, N., Ohnishi, S., Shimaoka, H. et al. Involvement of Recognition and Interaction of Carnitine Transporter in the Decrease of l-Carnitine Concentration Induced by Pivalic Acid and Valproic Acid. Pharm Res 23, 1729–1735 (2006). https://doi.org/10.1007/s11095-006-9002-9

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