Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps

Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps

MASAKO FUJIWARA,¹ ITIRO ANDO,² SHIGEAKI YAGI,³ MANABU NISHIZAWA,³ SHIRO OGUMA,⁴ KEISUKE SATOH,⁴ HIROSHI SATO² and YUTAKA IMAI¹

¹Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan
²Laboratory of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan
³Research and Development Center, Fuso Pharmaceutical Industries Ltd. Osaka, Osaka, Japan
4 Koujinkai Nagamachi Clinic, Sendai, Miyagi, Japan

Patients with renal failure undergoing hemodialysis (HD) are susceptible to muscle cramps during and after HD. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied by severe pain. Through HD, water-soluble vitamins are drawn out with water. Since biotin, a water-soluble vitamin, plays an essential role as one of the coenzymes in producing energy, we have hypothesized that deficiency of biotin may be responsible for HD-associated cramps. We previously reported that biotin administration ameliorated the muscle cramps, despite the elevated plasma biotin levels before HD and biotin administration, as judged by an enzyme-linked immunosorbent assay (ELISA). However, the ELISA measures not only biotin but also total avidin-binding substances (TABS) including biotin metabolites. In the present study, we determined biotin in HD patients as well as healthy controls, using a newly developed method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The plasma samples were collected from 28 HD patients (16 patients with cramps and 12 patients without cramps) before HD and biotin administration and from 11 controls. The results showed that the accumulation of biotin and TABS in plasma of HD patients compared to controls. Importantly, the levels of biotin metabolites, i.e. TABS subtracted by biotin, increased significantly in patients with cramps over those without cramps. Moreover, the levels of biotin metabolites were significantly higher in patients with a poor response to administered biotin, compared to those with a good response. We propose that accumulated biotin metabolites impair biotin's functions as a coenzyme.

keywords —— cramp; ELISA; hemodialysis; plasma biotin; UHPLC-MS/MS

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Tohoku J. Exp. Med., 2016, 239, 263-267

Correspondence: Masako Fujiwara, Ph.D., Department of Planning for Drug Development and Clinical Evaluation, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-aza-aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.

e-mail: fmasako@m.tohoku.ac.jp