Re: 타우린 경구투여 후 Cmax 1.5시간, 반감기 1시간... 타우린 약물역동학

[문형철]

J Amino Acids. 2010; 2010: 346237.

Published online 2010 Jun 29. doi: 10.4061/2010/346237

PMCID: PMC3275936

PMID: 22331997

Pharmacokinetics of Oral Taurine in Healthy Volunteers

Mohammadreza Ghandforoush-Sattari, 1, 2, 3, 4 , , , * Siminozar Mashayekhi, 1, 3, 4 , , Channarayapatna V. Krishna, 3, 4 , John P. Thompson, 3, 4 , and Philipp A. Routledge 3, 4 ,

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Abstract

Taurine, a sulfur-containing amino acid, is a normal constituent of the human diet. Little is known of the pharmacokinetics of taurine in man after oral administration. We studied the pharmacokinetics of 4 g taurine in eight healthy male volunteers (median age 27.5, range 22–45) following orally administration in the fasting state in the morning. Blood samples were taken at regular intervals and plasma taurine concentration was measured by a modified HPLC method. Data were subjected to noncompartmental analysis. Maximum plasma taurine concentration (Cmax) was measured at 1.5 ± 0.6 hr after administration as 86.1 ± 19.0 mg/L (0.69 ± 0.15 mmol). Plasma elimination half-life (T1/2) and the ratio of clearance/bioavailability (Cl/F) were 1.0 ± 0.3 hr and 21.1 ± 7.8 L/hr, respectively. Since taurine is occasionally used in therapeutics as a medicine, the pharmacokinetics and effects of oral taurine in healthy volunteers would be useful in the future studies of taurine in pharmacology and nutrition.

황 함유 아미노산인

타우린은

인간 식단의 정상적인 구성 성분입니다.

경구 투여 후 타우린의 약동학에 대해서는 알려진 바가 거의 없습니다.

우리는 8명의 건강한 남성 지원자(평균 연령 27.5세, 범위 22-45세)를 대상으로

아침 공복 상태에서

4g 타우린을 경구 투여한 후 약동학을 연구했습니다.

혈액 샘플을 일정한 간격으로 채취하고 혈장 타우린 농도를 수정된 HPLC 방법으로 측정했습니다. 데이터는 비구획 분석을 거쳤습니다.

투여 후 1.5 ± 0.6시간에

최대 혈장 타우린 농도(Cmax)를 측정한 결과

86.1 ± 19.0 mg/L(0.69 ± 0.15 mmol)로 나타났습니다.

혈장 제거 반감기(T1/2)와 청소율/생체 이용률(Cl/F)은

각각 1.0 ± 0.3시간,

21.1 ± 7.8 L/hr로 나타났습니다.

타우린은 때때로 치료제로서 의약품으로 사용되기 때문에 건강한 지원자에서 경구 타우린의 약동학 및 효과는 향후 약리학 및 영양학에서 타우린의 연구에 유용할 것입니다.

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1. Introduction

Taurine, a sulfur-containing amino acid, is a relatively nontoxic substance and a normal constituent of the human diet [1]. The diet provides most taurine either directly or by synthesis in the liver and brain from methionine or cysteine via cysteic acid or hypotaurine [2] or via cysteamine in the heart and kidney. Taurine stabilises membranes, modulates calcium transport, and is able to dissipate the toxic effects of hypochlorous acid (HOCl) by the formation of the relatively stable taurochloramine molecule, generated by myeloperoxidases from oxygen radicals. The ability of taurine to conjugate with xenobiotics, retinoic acid, and bile salts and its role as a major free amino acid in regulating the osmolality of cells are also examples of protective functions [3]. Obinata et al. showed ALT concentrations recovering in children with fatty liver after 6-months treatment with oral taurine administered daily [4]. Protective effects of taurine against arteriosclerosis [5], lung injury by oxidant gases [6], deleterious effects of various drugs such as tauromustine, an antitumor agent, [7], hepatotoxicity of sulfolithocholate [8], and its promotion of the recovery of leukocytes in irradiated rats [9] have already been studied on animals. The therapeutic effects of taurine on epilepsy [10], ischemia [11], obesity [12], diabetes [13], hypertension [14], Congestive heart failure [15], noxious effect of smoking [16], toxicity of methotrexate [17] myocardial infarction [18], alcoholic craving [19], and neurodegeneration in elderly [20] have also been reported. Taurine may protect membranes by detoxification of destructive compounds and/or by directly preventing alterations in membrane permeability [21]. Some foods or drinks, for example, Red Bull energy drink [22], boosters, eye drops, and eardrops, contain a considerable amount of taurine [23]. Little is known of the pharmacokinetics of taurine in man after oral administration. Such information is essential if a regimen for administration of this agent to patients (e.g., after paracetamol poisoning) is designed. A literature review revealed only one report concerning the pharmacokinetics of taurine performed by Zhang et al. [24] using 200 mg IV injection form of taurine in six patients with hypertension, but the paper was brief and only available in mandarin. We therefore studied the pharmacokinetics and effects of oral taurine in healthy volunteers that would be useful in the future studies of taurine in pharmacology and nutrition

1. 소개

황 함유 아미노산인 타우린은

비교적 무독성 물질이며 인간 식단의 정상적인 구성 성분입니다 [1].

식단을 통해 대부분의 타우린은

메티오닌이나 시스테인으로부터

간과 뇌에서 시스테산 또는 저타우린[2] 또는 심

장과 신장에서 시스테아민을 통해 직접 또는 합성을 통해 공급됩니다.

타우린은

세포막을 안정시키고

칼슘 수송을 조절하며,

산소 라디칼로부터 골수 산화 효소에 의해 생성되는 비교적 안정적인 타우로클로라민 분자를 형성하여

차아염소산(HOCl)의 독성 효과를 소멸시킬 수 있습니다.

타우린이

이종 생물, 레티노산 및 담즙 염과 결합하는 능력과

세포의 삼투압을 조절하는 주요 유리 아미노산으로서의 역할도 보호 기능의 예입니다 [3].

오비나타 등은 지방간이 있는 어린이에게 매일 경구 타우린을 6개월간 투여한 결과 ALT 농도가 회복되는 것을 보여주었습니다[4].

동맥경화에 대한 타우린의 보호 효과 [5],

산화 가스에 의한 폐 손상 [6],

항암제인 타우로무스틴과 같은 다양한 약물의 해로운 영향 [7],

설폴리토콜레이트의 간독성 [8],

방사선 조사 쥐의 백혈구 회복 촉진 [9] 등은

이미 동물 실험에서 연구된 바 있습니다.

간질 [10], 허혈 [11],

비만 [12], 당뇨병 [13], 고혈압 [14], 울혈성 심부전 [15],

흡연의 유해성 [16], 메토트렉세이트의 독성 [17] 심근경색 [18],

알코올 갈망 [19], 노인의 신경 퇴화 [20] 등에 대한

타우린의 치료 효과도 보고되고 있습니다.

타우린은

파괴적인 화합물을 해독하거나

막 투과성의 변화를 직접적으로 방지하여

막을 보호할 수 있습니다 [21].

예를 들어 레드불 에너지 드링크[22], 부스터, 안약, 귀약 등 일부 음식이나 음료에는 상당한 양의 타우린이 함유되어 있습니다[23]. 경구 투여 후 타우린의 약동학에 대해서는 알려진 바가 거의 없습니다.

이러한 정보는 환자에게 이 약제를 투여하는 요법(예: 파라세타몰 중독 후)을 설계하는 경우 필수적입니다. 문헌 검토 결과 타우린의 약동학에 관한 보고는 Zhang 등[24]이 6명의 고혈압 환자를 대상으로 200mg 정맥 주사 형태의 타우린을 사용하여 수행한 단 한 편의 논문이 있지만, 이 논문은 간략하고 중국어로만 되어 있습니다. 따라서 우리는 약리학 및 영양학에서 타우린의 향후 연구에 유용할 건강한 지원자를 대상으로 경구 타우린의 약동학 및 효과를 연구했습니다.

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2. Materials and Methods

Eight healthy male volunteers (age between 22–45 year, med. 27.5 and weight between 69–122 kg, med. 79.5 kg) were recruited from the general population after fully informed written consent and after getting approval from the ethics committee of Bro Taf Health Authority of Wales, UK. Each taurine capsule contained 1000 mg (0.008 moL) taurine, manufactured by Life Extension Foundation Buyers Club, Inc (USA). Taurine 4 g (32 mmoL) was administered orally to each volunteer in the fasting state in the morning. Subjects were asked to avoid taking any proprietary medicine including prescribed or recreational drugs, eating fish and any seafood or dairy products, and drinking “Red-Bull” 24 hours before and 48 hours after the study. They were given toast and jam with a cup of tea one hour after starting the study and a normal meal without any seafood at 4 hr of the study. Blood samples were taken (3 mL each time) at regular intervals over the following times: 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, and 8 hours and at 24 and 48 hours using cannulae in the brachial vain and collected into heparinised tubes. The samples were immediately centrifuged at 4°C at 3000 rpm. Plasma was removed using a Pasteur pipette and transferred into 5ml glass tubes and kept frozen at −20°C until analysis. Plasma taurine concentration was measured by a modified HPLC method. This method was sensitive enough, to quantify 150 pg/mL and detect 50 pg/mL of taurine ranging normally between 65 and 179 mmol/L (8–22 μg/mL) [25]. The pharmacokinetic parameters of area under the concentration curve (AUC0–8 h), maximum concentration (Cmax⁡), time of Cmax⁡ (Tmax⁡), plasma half-life (T1/2), volume of distribution (V), and the ratio of clearance/bioavailability (Cl/F) were calculated using WinNonlin (Version 1.5) software packages. The data were used to develop a noncompartmental pharmacokinetic model, which might be suitable for patient studies in the future. Since plasma taurine concentration returned to endogenous level after 8 hr of study, the data after 8 hr were ruled out of the pharmacokinetic analysis. In addition, since this was a study of kinetics of exogenously administered taurine, baseline endogenous concentrations of taurine in plasma (0.04 ± 0.0 mmoL) were also excluded from the study. Therefore, the changes in plasma taurine concentration from baseline were calculated.

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3. Results

Plasma taurine values from 0–48 hr in eight healthy volunteers after administration of 4 g taurine capsules are listed in Table 1. Data showed that endogenous plasma taurine concentrations before taking the taurine capsules ranged from 0.03 to 0.06 mmoL (mean 0.04 ± 0.0 mmoL). Time to reach maximum concentration ranged from 1 to 2.5 hr (mean 1.5 ± 0.6 hr) (absorption phase). The mean maximum plasma taurine concentration was 0.57 ± 0.05 mmoL. Plasma taurine concentrations returned to normal range at 8 hr (elimination phase) (Figure 1).

Figure 1

Linear plot of mean plasma taurine levels (mmoL) in eight healthy volunteers following administration of 4 g (32 mmoL) oral taurine.

Table 1

Plasma taurine concentrations (mmoL) in eight healthy volunteers after administration of 4 g (32 mmoL) oral taurine.

Time (hr)SubjectsMeanSEM12345678

0	0.06	0.04	0.03	0.03	0.03	0.04	0.06	0.04	0.04	0.00
0.5	0.31	0.44	0.22	0.41	0.04	0.04	0.23	0.19	0.24	0.05
1	0.62	0.57	0.61	0.84	0.20	0.06	0.35	0.80	0.51	0.10
1.5	0.46	0.56	0.74	0.75	0.60	0.30	0.53	0.62	0.57	0.05
2	0.32	0.44	0.93	0.51	0.72	0.77	0.32	0.43	0.56	0.08
2.5	0.27	0.41	0.66	0.36	0.64	0.84	0.24	0.37	0.47	0.08
3	0.23	0.27	0.40	0.28	0.42	0.68	0.21	0.23	0.34	0.06
3.5	0.18	0.22	0.36	0.25	0.33	0.49	0.20	0.20	0.28	0.04
4	0.11	0.16	0.26	0.18	0.27	0.41	0.17	0.18	0.22	0.03
5	0.07	0.10	0.16	0.11	0.20	0.32	0.07	0.03	0.13	0.03
6	0.06	0.08	0.08	0.10	0.10	0.23	0.06	0.04	0.09	0.02
7	0.06	0.07	0.08	0.07	0.09	0.14	0.06	0.03	0.07	0.01
8	0.06	0.06	0.05	0.04	0.07	0.05	0.06	0.05	0.05	0.00
24	0.06	0.04	0.03	0.02	0.04	0.06	0.07	0.06	0.05	0.01
48	0.05	0.04	0.04	0.02	0.02	0.06	0.09	0.04	0.05	0.01

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Mean changes in plasma taurine concentrations from baseline showed that the absorption phase for taurine after oral administration of 4 g taurine capsules took 1.5 hr to reach the peak concentration (0.53 ± 0.1 mmoL) and then returned to normal range (0.04 ± 0.0 mmoL) in 6.5 hr (Figure 1). The pharmacokinetic parameters of taurine after oral administration of 4 g taurine capsules are shown in Table 2. Plasma taurine concentration peaked to 59.0–112.6 mg/L (mean 86.1 ± 19.0) at 1–2.5 hr of study, plasma elimination half-life ranged from 0.7 to 1.4 hr (mean 1.0 ± 0.3), volume of distribution ranged from 19.8 to 40.7 L (mean 30.0 ± 7.6), ratio of clearance/bioavailability (Cl/F) ranged from 14.0 to 34.4 L/hr (mean 21.1 ± 7.8), and area under curve between 0–8 hr (AUC) ranged from 116.0 to 284.5 mg·hr/L (mean 206.3 ± 63.9).

Table 2

Pharmacokinetic parameters of taurine after oral administration of 4 g (32 mmoL) taurine capsules.

SubjectsCmax⁡ (mg/L)Tmax⁡ (hr)AUC(0-8 hr) (mg·hr/L)Ke (hr−1)T1/2 (hr)V (L)Cl/F (L/hr)

1	69.7	1	127.7	0.8	0.8	37.8	31.2
2	66.7	1	198.0	0.5	1.4	40.7	19.5
3	112.6	2	281.4	0.6	1.1	22.1	14.0
4	100.4	1	235.0	0.6	1.1	26.8	16.9
5	86.1	2	232.0	0.5	1.4	32.5	16.6
6	99.5	2.5	284.5	0.7	1	19.8	14.0
7	59.0	1.5	116.0	1.0	0.7	34.8	34.4
8	94.8	1.0	175.9	0.9	0.8	25.1	22.2
Mean	86.1	1.5	206.3	0.7	1.0	30.0	21.1
SD	19.0	0.6	63.9	0.2	0.3	7.6	7.8
Range	59.0–112.6	1–2.5	116.0–284.5	0.5–1.0	0.7–1.4	19.8–40.7	14.0–34.4

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4. Discussion

Taurine has already been used intravenously in humans in doses of up to 5 g [26] and 2–6 g/day orally for a period of 6 months in children with fatty liver [4] without any toxic side effect. In the human adult, about one-fourth of bile acids are conjugated with taurine and a small fraction of taurine is also converted to isethionate by either bacterial or tissue enzymes and may be converted in part to sulphate, CO2, water, and ammonia, the last being converted to urea [27]. Total body taurine is regulated by the kidney. Taurine is a major urinary amino acid in humans because the capacity of renal uptake is low [2, 28]. Daily taurine losses in urine are diet-dependent but generally range from 65 to 250 mg (0.5–2.0 mmoL) [27]. With few exceptions, animal [2] and human [15] studies have demonstrated that taurine, even in high doses, is generally free of any serious adverse effects. In the present study, no significant change in the systolic or diastolic blood pressure and pulse rate was observed during the study and the volunteers had no complaint during the study. In the present study, data showed that oral taurine was absorbed from the gastrointestinal tract 1–2.5 hr following administration and then eliminated from plasma by first order kinetics. Even though the volunteers had been asked to avoid eating anything before coming to the trial, two subjects (3 and 6), whose absorption phase took 2 and 2.5 hr, respectively, may not have taken the drug with an empty stomach (Figure 2).

4. 토론

타우린은

이미 사람에게 최대 5g[26],

지방간이 있는 어린이에게 6개월 동안 2-6g/일 경구 복용으로

독성 부작용 없이 정맥 내로 사용되어 왔습니다[4].

성인의 경우

담즙산의 약 4분의 1이 타우린과 접합되어 있으며

타우린의 일부도 박테리아 또는 조직 효소에 의해 이세티오네이트로 전환되고

일부는 황산염, CO2, 물, 암모니아로 전환되며

마지막에는 요소로 전환될 수 있습니다[27].

황 함유 아미노산 경로의 최종 생성물인 타우린은 간에서 담즙산(BA)과 접합됩니다. 타우린 합성과 BA 접합 모두에서 속도 제한 효소는 BA 항상성을 촉진하는 핵 수용체 FXR에 의해 조절될 수 있습니다. 그러나 BA 합성의 종 차이로 인해 인간과 생쥐에서 각각 천연 FXR 작용제 또는 길항제로 작용하는 BA가 존재하기 때문에 논란의 여지가 있습니다. 본 연구에서는 인간과 유사한 BA 구성을 가진 Cyp2a12-/-/Cyp2c70-/- 마우스와 야생형(WT) 마우스를 비교하여 간 내 두 경로에 대한 서로 다른 BA 구성의 영향을 평가했습니다. DKO 간에는 천연 FXR 길항성 BA가 풍부하게 포함되어 있으며, 타우린 결합 BA 비율과 타우린 농도는 유의하게 증가한 반면, 천연 FXR 길항성 BA가 있는 WT 간에는 총 BA 농도가 유의하게 감소했습니다. BA 아미네이션에 관여하는 효소인 Bacs와 Baat, 타우린 합성에 관여하는 Cdo와 Fmo1, 그리고 Fxr과 그 표적 유전자인 Shp의 mRNA 발현 수준은 DKO 간에서 WT 간보다 유의하게 높았다. 본 연구는 간에서 인간과 유사한 BA 구성을 가진 모델을 사용하여 생쥐에서 처음으로 타우린 합성과 BA 아미데이션 경로가 모두 FXR 활성화에 의해 상향 조절된다는 것을 확인했습니다.

체내 타우린은

신장에 의해 조절됩니다.

타우린은

신장의 흡수 능력이 낮기 때문에

인간의 주요 소변 아미노산입니다 [2, 28].

소변에서의 일일 타우린 손실은

식단에 따라 다르지만

일반적으로 65~250mg(0.5~2.0mmoL) 범위입니다[27].

몇 가지 예외를 제외하고, 동물[2] 및 인간[15] 연구에 따르면 타우린은 고용량으로도 일반적으로 심각한 부작용이 없는 것으로 나타났습니다. 본 연구에서는 연구 기간 동안 수축기 또는 이완기 혈압과 맥박수에서 유의미한 변화가 관찰되지 않았으며 지원자들은 연구 기간 동안 아무런 불만을 제기하지 않았습니다.

본 연구에서 데이터에 따르면

경구 타우린은 투여 후 1-2.5 시간 후에

위장관에서 흡수된 후

일차 동역학에 의해 혈장에서 제거되는 것으로 나타났습니다.

지원자들에게 임상시험에 오기 전에 아무것도 먹지 말라고 요청했음에도 불구하고,

흡수 단계가 각각 2시간과 2.5시간이 걸린 두 명의 피험자(3명과 6명)는 공복 상태에서 약물을 복용했을 수 있습니다(그림 2).

Figure 2

Changes in plasma taurine (mmoL) from baseline in eight healthy volunteers following administration of 4 g (32 mmoL) oral taurine.

Plasma taurine returned to endogenous concentrations after 6–8 hr of study. Therefore, there was no need to follow up the drug in plasma after 8 hr.

건강한 지원자 8명을 대상으로 4g(32mmoL)의 경구 타우린을 투여한 후 기준치 대비 혈장 타우린(mmoL)의 변화.
혈장 타우린은 연구 6~8시간 후 내인성 농도로 회복되었습니다. 따라서 8시간 후 혈장 내 약물 농도를 추적 관찰할 필요가 없었습니다.

문헌 검토 결과 타우린의 약동학에 관한 보고는 단 한 건에 불과했습니다 [24]. Zhang 등은 6명의 고혈압 환자와 6명의 건강한 지원자를 대상으로 200mg 정맥 주사의 약동학을 연구했습니다. 장 등의 연구에서 타우린의 혈장 반감기와 분포량은 각각 3.85 ± 0.05분과 9.6 ± 3.2L였습니다. 그러나 이들은 혈장 타우린 농도를 20분 동안만 추적했기 때문에 경구 흡수 후 타우린의 흡수 단계에 의해 가려진 알파 단계를 조사했을 가능성이 높습니다. 사람의 독성 물질로부터 세포를 보호하는 최적의 경구 타우린 용량을 밝히기 위해서는 추가 연구가 필요합니다.

A literature review revealed only one report concerning the pharmacokinetics of taurine [24]. Zhang et al. studied the pharmacokinetics of an IV injection of a 200 mg bolus dose on six hypertensive human patients and six healthy volunteers. Plasma half-life and volume of distribution of taurine in Zhang et al.'s was 3.85 ± 0.05 min and 9.6 ± 3.2 L, respectively. However, they only followed the plasma taurine concentrations for 20 min, and therefore, they were probably examining an alpha phase which was obscured by the absorption phase for taurine after oral absorption. Further studies are necessary to elucidate the optimum dose of oral taurine for protecting cells against toxic agents in human.

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Acknowledgments

The authors wish to thank to Dr. DC Buss, Dr. A. Hutchings, Mrs. F. Harry, Miss M. Tessa Hut, and the personnel of the Toxicology Department and Poisons Unit at Llandough Hospital and Pharmacology Department at the University Hospital of Wales for helping them in the development of analysis techniques and running the necessary clinical investigations and the healthy volunteers for taking part in the clinical investigations.

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References

1. Huxtable R, Sebring L. Cardiovascular actions of taurine. In: Kuriyama K, Huxtable R, Iwata H, editors. Sulfur Amino Acids Biochemical Aspects. New York, NY, USA: Alan R. Liss; 1983. pp. 5–37. [Google Scholar]

2. Jacobsen JG, Smith LH. Biochemistry and physiology of taurine and taurine derivatives. Physiological Reviews. 1968;48(2):424–511. [PubMed] [Google Scholar]

3. Waterfield CJ, Turton JA, Scales MD, Timbrell JA. Taurine, a possible urinary marker of liver damage: a study of taurine excretion in carbon tetrachloride-treated rats. Archives of Toxicology. 1991;65(7):548–555. [PubMed] [Google Scholar]

4. Obinata K, Maruyama T, Hayashi M, Watanabe T, Nittono H. Effect of taurine on the fatty liver of children with simple obesity. Advances in Experimental Medicine and Biology. 1996;403:607–613. [PubMed] [Google Scholar]

5. Yamauchi-Takihara K, Azuma J, Kishimoto S. Taurine protection against experimental arterial calcinosis in mice. Biochemical and Biophysical Research Communications. 1986;140(2):679–683. [PubMed] [Google Scholar]

6. Gordon RE. The effects of NO2 on ionic surface charge on type I pneumocytes of hamster lungs. American Journal of Pathology. 1985;121(2):291–297. [PMC free article] [PubMed] [Google Scholar]

7. Pierson HF, Fisher JM, Rabinovitz M. Modulation by taurine of the toxicity of taumustine, a compound with antitumor activity. Journal of the National Cancer Institute. 1985;75(5):905–909. [PubMed] [Google Scholar]

8. Dorvil NP, Yousef IM, Tuchweber B, Roy CC. Taurine prevents cholestasis induced by lithocholic acid sulfate in guinea pigs. American Journal of Clinical Nutrition. 1983;37(2):221–232. [PubMed] [Google Scholar]

9. Abe M, Takahashi M, Takeuchi K, Fukuka M. Studies on the significance of taurine in radiation injury. Radiation Research. 1968;33(3):563–573. [PubMed] [Google Scholar]

10. Barbeau A, Donaldson J. Zinc, taurine, and epilepsy. Archives of Neurology. 1974;30(1):52–58. [PubMed] [Google Scholar]

11. McCarty MF. A proposal for the locus of metformin’s clinical action: potentiation of the activation of pyruvate kinase by fructose-1,6-diphosphate. Medical Hypotheses. 1999;52(2):89–93. [PubMed] [Google Scholar]

12. Fennessy FM, Moneley DS, Wang JH, Kelly CJ, Bouchier-Hayes DJ. Taurine and vitamin C modify monocyte and endothelial dysfunction in young smokers. Circulation. 2003;107(3):410–415. [PubMed] [Google Scholar]

13. Chauncey KB, Tenner TE, Jr., Lombardini JB, et al. The effect of taurine supplementation on patients with type 2 diabetes mellitus. Advances in Experimental Medicine and Biology. 2003;526:91–96. [PubMed] [Google Scholar]

14. Fujita T, Ando K, Noda H, Ito Y, Sato Y. Effects of increased adrenomedullary activity and taurine in young patients with borderline hypertension. Circulation. 1987;75(3):525–532. [PubMed] [Google Scholar]

15. Azuma J, Sawamura A, Awata N, et al. Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial. Clinical Cardiology. 1985;8(5):276–282. [PubMed] [Google Scholar]

16. Wilde MI, Wagstaff AJ. Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs. 1997;53(6):1038–1053. [PubMed] [Google Scholar]

17. Çetiner M, Şener G, Şehirli AÖ, et al. Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicology and Applied Pharmacology. 2005;209(1):39–50. [PubMed] [Google Scholar]

18. Singh RB, Kartikey K, Charu AS, Niaz MA, Schaffer S. Effect of taurine and coenzyme Q10 in patients with acute myocardial infarction. Advances in Experimental Medicine and Biology. 2003;526:41–48. [PubMed] [Google Scholar]

19. Wallace DR, Dawson R., Jr. Decreased plasma taurine in aged rats. Gerontology. 1990;36(1):19–27. [PubMed] [Google Scholar]

20. Barbeau A, Inoue N, Tsukada Y, Butterworth RF. The neuropharmacology of taurine. Life Sciences. 1975;17(5):669–677. [PubMed] [Google Scholar]

21. Kendler BS. Taurine: an overview of its role in preventive medicine. Preventive Medicine. 1989;18(1):79–100. [PubMed] [Google Scholar]

22. Alford C, Cox H, Wescott R. The effects of red bull energy drink on human performance and mood. Amino Acids. 2001;21(2):139–150. [PubMed] [Google Scholar]

23. Gupta RC, Win T, Bittner S. Taurine analogues; a new class of therapeutics: retrospect and prospects. Current Medicinal Chemistry. 2005;12(17):2021–2039. [PubMed] [Google Scholar]

24. Zhang Y, Sun Z, Shi X. Pharmacokinetics and pharmacodynamics of the effects of taurine on human blood pressure and heart rate. Journal of Clinical and Hospital Pharmacy. 1998;18:106–107. [Google Scholar]

25. Ghandforoush-Sattari M, Mashayekhi S, Nemati M, Routledge PA. A rapid determination of taurine in human plasma by LC. Chromatographia. 2009;69(11-12):1427–1430. [Google Scholar]

26. Milei J, Ferreira R, Llesuy S, Forcada P, Covarrubias J, Boveris A. Reduction of reperfusion injury with preoperative rapid intravenous infusion of taurine during myocardial revascularization. American Heart Journal. 1992;123(2):339–345. [PubMed] [Google Scholar]

27. Sturman JA, Hepner GW, Hofmann AF, Thomas PJ. Metabolism of [35S]taurine in man. Journal of Nutrition. 1975;105(9):1206–1214. [PubMed] [Google Scholar]

28. Chesney RW. Taurine: its biological role and clinical implications. Advances in Pediatrics. 1985;32:1–42. [PubMed] [Google Scholar]