学位授与機関 北海道医療大学

北海道医療大学学術リポジトリ

TDMへの応用を目指した血漿中薬物濃度と臨床効果 に関する研究

著者 野田 久美子

学位名 博士（薬学）

学位授与機関 北海道医療大学

学位授与年度 平成25年度 学位授与番号 30110乙第102号

URL http://id.nii.ac.jp/1145/00004799/

TDM ࡬ࡢᛂ⏝ࢆ┠ᣦࡋࡓ

⾑₢୰⸆≀⃰ᗘ࡜⮫ᗋຠᯝ࡟㛵ࡍࡿ◊✲

ᖹᡂ㸰㸳ᖺᗘ

㔝 ⏣ ஂ ⨾ Ꮚ

Summary

A modified method for the quantitative determination of bepridil and unbound micafungin in human plasma is herein described. The relationship between the concentration of both drugs in human plasma and the clinical effects were also investigated.

In the bepridil studies, the mobile phase consisted of 50 mM phosphate buffer (pH 3.0): methanol:

acetonitrile: triethylamine (57:3:40:1, v/v). The samples were fractionated on a C8-3 column (150 × 4.6 mm, 5 ȝm) using a flow rate of 0.9 mL/min. 1-Naphthol was used as the internal standard (IS). Bepridil was detected by UV spectroscopy at 254 nm. The relationship was then evaluated between the plasma concentration of bepridil (Cbep) and the effects transformed from atrial fibrillation (AF) to sinus rhythm (SR) for 36 patients with AF. The patients were treated orally with 100, 150 or 200 mg/day bepridil. In the introduction stage (first 14 days after starting therapy, n=15), when 150, 200, 250 or 300 ng/mL were set as a boundary value, the efficacy of bepridil was significantly higher in all patients with Cbep above the

boundary value than in those with Cbep below the boundary value (P<0.05). During the maintenance stage (3 months after starting therapy, n = 22), the efficacy of bepridil was significantly higher in patients with Cbep above 300 ng/mL (P=0.04). The clinical efficacy of bepridil was closely related to Cbep. The target value of Cbep to obtain a clinical benefit was approximately 300 ng/mL. These results suggest that monitoring Cbep should be useful in the treatment of patients with AF.

In the micafungin studies, the mobile phase consisted of 50 mM phosphate buffer (pH 3.0):

tetrahydrofuran (65:35, v/v). Samples were fractionated on a C-18 column. The fluorescence detection wavelengths of excitation and emission were set at 273 nm and 464 nm, respectively.

1-Hydroxy-2-naphthoic acid was used as the IS. The peak height ratio of micafungin/IS on a 5-point calibration curve was linear from 0.004 to 0.08 ȝg/mL (r=0.999, P<0.001). In addition, the concentrations of unbound and total micafungin were measured in the plasma of 11 patients treated with micafungin for fungal infection. In total, 99 samples were collected. A correlation was observed between the concentrations of unbound and total micafungin in plasma (r =0.896, P<0.001). Furthermore, the relationship between the plasma concentration of micafungin and the clinical effects for 3 patients suspected to be infected with mycosis was investigated. The patients were treated with micafungin (150 mg/day), resulting in concentrations of unbound and total micafungin being above 0.0069 and 2.5 ȝg/mL, respectively.

Micafungin was thus diagnosed as effective for the patients in this study. In case 1, the aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels increased when the plasma concentration of unbound and total micafungin rose just prior to injection. Therefore, it was suggested that delaying excretion and/or metabolism of micafungin in the liver causes a rise in the plasma concentration of micafungin. In all cases, the plasma concentration of unbound micafungin was above the minimum inhibitory concentration of the pathogenic fungi.

Conclusion: Our results suggest that the clinical effect of bepridil depends on the concentration in plasma.

Furthermore, it appears possible that the unbound concentration of micafungin in plasma affects the antifungal efficacy in patients. The pharmacokinetics of bepridil display large individual differences, and it is thus important to set the target concentration of micafungin in plasma for achieving effective antifungal therapy. Therefore, the therapeutic drug monitoring of bepridil and micafungin appear useful in antifungal treatment.

Ꮫ఩ㄽᩥࡢᇶ♏࡜࡞ࡿሗᩥ

(1) Noda K., Narayama Y., Goto Y., Kobayashi M., Kuronuma H., Iwai S., Itoh K., Katoh N., Tadano K., The LC method for quantifying bepridil in human plasma using 1-naphtol as the internal standard. J. Chromatogr. Sci., 49, 519-523 (2011).

(2) Noda K., Gotoh Y., Tanioka S., Narayama Y., Kobayashi M., Iwai S.,

Katoh N., Tadano K., The relationship between the plasma concentration of bepridil and its efficacy in the treatment of atrial fibrillation in Japanese

patients. Biol. Pharm. Bull., 35, 672-676 (2012).

(3) Noda K., Narayama Y., Gotoh Y., Kobayashi M., Iwai S., Katoh N., Tadano K., The clinical efficacy of bepridil depends on its concentration in human plasma.

TDM ◊✲ , 29, 109-114 (2012).

(4) 㔝⏣ஂ⨾Ꮚ, ᶓᒣᩄ⣖, ⛅ᒣஓᑍྐ, ၏㔝㈉ྖ, HPLCἲ࡟ࡼࡿ⾑₢୰㐟㞳ᆺ

࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ ᐃἲࡢᵓ⠏࡜⾑₢୰⥲࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ࡜ࡢ㛵ಀ.

YAKUGAKU ZASSHI, 133, 397-404 (2013).

ཧ ⪃ ㄽ ᩥ

(1) 㔝⏣ஂ⨾Ꮚ, ୖ⏣᫭, 㯮἟༤ྐ, ᒾ஭᪂἞, ఀ⸨຾⨾, ᩧ⸨ᐜᏊ, ᑠ಴⁠᫂, ᑠᯘ㐨ஓ, ၏㔝㈉ྖ, Antimicrobial Use Density ࢆ⏝࠸ࡓὀᑕ⏝ᢠ⳦⸆࠾ࡼࡧ ᢠ┿⳦⸆ࡢ౑⏝ືྥኚ໬ࡢ㛗ᮇⓗゎᯒ࡜ࡑࡢせᅉ I. ⎔ቃឤᰁㄅ , 24, 332-336 (2009).

(2) 㔝⏣ஂ⨾Ꮚ, ୖ⏣᫭, 㯮἟༤ྐ, ᒾ஭᪂἞, ఀ⸨຾⨾, ᩧ⸨ᐜᏊ, ᑠ಴⁠᫂, ᑠᯘ㐨ஓ, ၏㔝㈉ྖ, Antimicrobial Use Density ࢆ⏝࠸ࡓὀᑕ⏝ᢠ⳦⸆࠾ࡼࡧᢠ┿⳦

⸆ࡢ౑⏝ືྥኚ໬ࡢ㛗ᮇⓗゎᯒ࡜ࡑࡢせᅉ II. ⎔ቃឤᰁㄅ , 24, 400-404 (2009).

(3)

ᶓᒣᩄ⣖, ⸨⃝┿୍, Ώ㑔༤ᩥ, ⠛ཎᚭ, ⸨㇂ዲᘯ, ⛅ᒣஓᑍྐ,

ᑠᯘ㐨ஓ, ၏㔝㈉ྖ, ⫢ᶵ⬟᳨ᰝ್ࡢኚ໬࡜ඹ࡟⾑୰ micafungin ⃰ᗘࡀୖ᪼ࡋࡓ῝

ᅾᛶ┿⳦⑕ࡢ୍⑕౛. TDM ◊✲ , 27, 163-167 (2010).

(4) 㔝⏣ஂ⨾Ꮚ, ⠛ཎᚭ, ᶓᒣᩄ⣖, ⸨⃝┿୍, Ώ㑔༤ᩥ, ⸨㇂ዲᘯ, ཎ⏣ᩄஅ,

⛅ᒣஓᑍྐ, ᑠᯘ㐨ஓ, ၏㔝㈉ྖ, Candida ᒀ㊰ឤᰁ⑕࡟ micafungin ࡀ᭷ຠ࡛࠶ࡗ

ࡓ 2 ⑕౛. TDM ◊✲ , 28,114-118 (2011).

␎ㄒ⾲

Af Atrial fibrillation 㸸ᚰᡣ⣽ື

AFL Atrial flutter㸸ᚰᡣ⢒ື

ALT Alanine amino transferase㸸࢔ࣛࢽࣥ࢔࣑ࣀࢺࣛࣥࢫࣇ࢙࣮ࣛࢮ

AST Aspartate amino transferase㸸࢔ࢫࣃࣛࢠࣥ㓟࢔࣑ࣀࢺࣛࣥࢫࣇ࢙࣮ࣛࢮ

AUC Area under the blood concentration-time curve㸸

⾑୰⃰ᗘ-᫬㛫᭤⥺ୗ㠃✚

AUD Antimicrobial use density㸸ᢠ⳦⸆౑⏝ᐦᗘ BUN Blood urea nitrogen㸸⾑୰ᒀ⣲❅⣲

Ccr Creatinine clearance㸸ࢡࣞ࢔ࢳࢽࣥࢡࣜ࢔ࣛࣥࢫ

CDC Centers for disease control and prevention㸸⡿ᅜ⑌⑓ண㜵⟶⌮ࢭࣥࢱ࣮

C/D Concentration/dose

C

Maximum concentration㸸᭱㧗⾑୰⃰ᗘ C

Minimum concentration㸸᭱ᑠ⾑୰⃰ᗘ

CT Computed tomography㸸ࢥࣥࣆ࣮ࣗࢱ᩿ᒙ᧜ᙳ

DDD Defined daily dose

ESBL Extended-spectrum

ESRD End stage renal disease㸸ᮎᮇ⭈୙඲

FPIA Fluorescence polarization immunoassay㸸⺯ග೫ග࢖࣒ࣀ࢔ࢵࢭ࢖

HIV Human immunodeficiency virus㸸ࣄࢺච␿୙඲࢘࢖ࣝࢫ

HPLC High-performance liquid chromatography㸸㧗㏿ᾮయࢡ࣐ࣟࢺࢢࣛࣇ࢕࣮

ICD Implantable cardioverter defibrillator㸸᳜㎸ࡳᆺ㝖⣽ື⿦⨨

ICT Infection control team㸸ឤᰁไᚚࢳ࣮࣒

IPA Invasive pulmonary aspergillosis㸸౵くᛶ⫵࢔ࢫ࣌ࣝࢠࣝࢫ⑕

IS Internal standard㸸ෆᶆ‽≀㉁

LVFX Levofloxacin㸸ࣞ࣎ࣇࣟ࢟ࢧࢩࣥ

MCFG Micafungin㸸࣑࢝ࣇ࢓ࣥࢠࣥ

MDRP Multi-drug resistant Pseudomonas aeruginosa㸸ከ๣⪏ᛶ⥳⮋⳦

MEPM Meropenem㸸࣓ࣟ࣌ࢿ࣒

MFC Minimum fungicidal concentration㸸᭱ᑠẅ┿⳦⃰ᗘ MIC Minimal inhibitory concentration㸸᭱ᑠⓎ⫱㜼Ṇ⃰ᗘ

MRSA Methicillin-resistant Staphylococcus aureus㸸࣓ࢳࢩࣜࣥ⪏ᛶ㯤Ⰽࣈࢻ࢘⌫⳦

PAF Paroxysmal atrial fibrillation㸸Ⓨసᛶᚰᡣ⣽ື

PAFE Post antifungal effect

PIPC/TAZ Piperacillin/tazobactam㸸ࣆ࣌ࣛࢩࣜࣥ/ࢱࢰࣂࢡࢱ࣒

PK/PD Pharmacokinetics/Pharmacodynamics㸸⸆≀ືែᏛ/⸆ຊᏛ

Scr Serum creatinine㸸⾑Ύࢡࣞ࢔ࢳࢽࣥ

S/N Signal/Noise

SR Sinus rhythm㸸Ὕㄪᚊ

SSI Surgical site infection㸸ᡭ⾡㒊఩ឤᰁ T-bil Total bilirubin㸸⥲ࣅࣜࣝࣅࣥ⃰ᗘ

TDM Therapeutic drug monitoring㸸἞⒪⸆≀ࣔࢽࢱࣜࣥࢢ TdP Torsades de pointes

TEIC Teicoplanin㸸ࢸ࢖ࢥࣉࣛࢽࣥ

Tmax Maximum drug concentration time㸸᭱㧗⾑୰⃰ᗘ฿㐩᫬㛫

VCMC Vancomycin㸸ࣂࣥࢥ࣐࢖ࢩࣥ

WBC White blood cell㸸ⓑ⾑⌫

WHO World Health Organization㸸ୡ⏺ಖ೺ᶵ㛵

┠ ḟ

ᗎㄽ ͐͐ 1

➨

❶ ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲࡢᵓ⠏ ͐͐ 7

➨

⠇ ⥴ゝ ͐͐ 7

➨

⠇ ᪉ἲ ͐͐ 7

➨

㡯 ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ ͐͐ 7 ➨

㡯 ⮫ᗋᝈ⪅࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃ ͐͐11

➨

⠇ ⤖ᯝ ͐͐12

➨

⠇ ⪃ᐹ ͐͐18

➨

❶ ⤒ཱྀᢞ୚ᚋ࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡢࣔࢽࢱࣜࣥࢢ࣏࢖ࣥࢺࡢጇᙜᛶ࡟

㛵ࡍࡿ᳨ウ ͐͐21

➨

⠇ ⥴ゝ ͐͐21

➨

⠇ ᪉ἲ ͐͐22

➨

⠇ ⤖ᯝ ͐͐23

➨

㡯 ࣋ࣉࣜࢪࣝ⤒ཱྀᢞ୚ᚋࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ᥎⛣࡜ಶయෆኚື͐͐23 ➨

㡯 ᢞ୚┤๓⃰ᗘ࡜᭷ຠᛶ࠾ࡼࡧ๪స⏝ࡢ㛵ಀ ͐͐27

͐͐27

͐͐29

͐͐31

➨

⠇ ⪃ᐹ ͐͐33

➨

❶ ࣋ࣉࣜࢪࣝᑟධᮇ࠾ࡼࡧ⥔ᣢᮇ࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ࡜᭷ຠᛶࡢ㛵ಀ

͐͐37

➨

⠇ ⥴ゝ ͐͐37

➨

⠇ ᪉ἲ ͐͐38

➨

⠇ ⤖ᯝ ͐͐39

➨

㡯 ᝈ⪅⫼ᬒ ͐͐39

➨

㡯 ࣋ࣉࣜࢪࣝ࡟ࡼࡿ⸆≀⒪ἲᑟධᮇ࡟࠾ࡅࡿ⾑₢୰⃰ᗘ࡜᭷ຠᛶࡢホ౯

͐͐40

➨

㡯 ࣋ࣉࣜࢪࣝ࡟ࡼࡿ⸆≀⒪ἲ⥔ᣢᮇ࡟࠾ࡅࡿ⾑₢୰⃰ᗘ࡜᭷ຠᛶࡢホ౯

͐͐44

➨

⠇ ⪃ᐹ ͐͐48

➨

❶ ⾑₢୰㐟㞳ᆺ࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ ᐃἲࡢᵓ⠏ ͐͐53

➨

⠇ ⥴ゝ ͐͐53

➨

⠇ ᪉ἲ ͐͐54

➨

㡯 ⾑₢୰㐟㞳ᆺ࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ ᐃἲ ͐͐54 ➨

㡯 ⾑₢୰⥲࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ ᐃ ͐͐57

➨

⠇ ⤖ᯝ ͐͐58

➨

⠇ ⪃ᐹ ͐͐62

➨

❶ ⾑₢୰࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘ᥎⛣࡜ᝈ⪅ಶࠎ࡟࠾ࡅࡿ⮫ᗋຠᯝࡢ᳨ウ ͐͐65

➨

⠇ ⥴ゝ ͐͐65

➨

⠇ ᪉ἲ ͐͐66

➨

⠇ ⤖ᯝ ͐͐67

͐͐67

͐͐70

㸧 ͐͐73

➨

⠇ ⪃ᐹ ͐͐75

⥲ᣓ ͐͐80

ᘬ⏝ᩥ⊩ ͐͐83

ㅰ㎡ ͐͐91

1

ᗎㄽ

἞⒪⸆≀ࣔࢽࢱࣜࣥࢢ (therapeutic drug monitoring: TDM) ࡢ⮫ᗋ࡬ࡢᑟධࡣ , ࣇ࢙ࢽࢺ

࢖ࣥࡢ᭷ຠ⾑୰⃰ᗘ⠊ᅖࡢ◊✲࠿ࡽ࡜ࡉࢀ࡚࠸ࡿ .

1960 㹼 1970 ᖺ௦࡟࠿ࡅ࡚⸆≀㏿ᗘㄽ ࡢᡭἲࢆ⏝࠸࡚⾑୰⃰ᗘࢹ࣮ࢱࢆฎ⌮ࡋ , ⸆≀἞⒪ࡢ㐺ṇ໬࡟ດࡵࡿࡇ࡜ࡀᥦၐࡉࢀࡓ .

ࡇࢀࢆࡶ࡜࡟ ,  ᐃࡋࡓᝈ⪅ࡢ⾑୰⸆≀⃰ᗘࢹ࣮ࢱࢆゎᯒࡋ࡚἞⒪ຠᯝ࡜࡜ࡶ࡟⾑୰⸆≀

⃰ᗘࢆࣔࢽࢱࣜࣥࢢࡋࡘࡘ , ᝈ⪅ಶࠎ࡟࠶ࢃࡏ࡚⸆≀ᢞ୚ィ⏬ࢆ❧᱌ࡍࡿ᪉ἲㄽࢆ TDM

࡜࿧ࡪࡼ࠺࡟࡞ࡗࡓ .

᪥ᮏ࡛ࡣࢧࣝࣇ࢓๣ࡢ⾑୰⃰ᗘ ᐃࡣ᪩ᮇ࠿ࡽᐇ᪋ࡉࢀ࡚࠸ࡓࡶࡢࡢ , ⮫ᗋ࡟࠾ࡅࡿ

TDM ࡢጞࡲࡾࡣ 1960 㹼 1970 ᖺ௦࡟⾜ࢃࢀࡓᢠ࡚ࢇ࠿ࢇ⸆ࡢ TDM ◊✲࡛࠶ࡿ . ࡇࡢ◊✲

ᴗ⦼࡟ࡼࡾ་⒪࡟࠾ࡅࡿ TDM ࡢᚲせᛶࡀㄆࡵࡽࢀ , 1980 ᖺ࡟㌄࠺ࡘ⑓἞⒪⸆࡛࠶ࡿⅣ 㓟ࣜࢳ࣒࢘ࡢ⾑୰⃰ᗘ ᐃࡀึࡵ࡚≉ᐃ⸆๣἞⒪⟶⌮ᩱ࡜ࡋ࡚ಖ㝤Ⅼᩘ໬ࡉࢀࡓ . ⩣

1981 ᖺ࡟ࡣᢠ࡚ࢇ࠿ࢇ⸆࡜ࢪࢠࢱࣜࢫ〇๣ࡶᑐ㇟⸆≀࡜࡞ࡗ࡚࠸ࡿ . ௨㝆 , ᑐ㇟⸆≀ࡣᣑ

኱ࡉࢀ , ⮫ᗋ࡛⾑୰⸆≀⃰ᗘࡢࣔࢽࢱࣜࣥࢢࡀᗈࡃ⾜ࢃࢀࡿࡼ࠺࡟࡞ࡗࡓ . ࡑࢀ࡟ࡼࡾ ,

⸆≀ࡢຠᯝࡸ๪స⏝ࡢண  , ࡼࡾຠᯝⓗ࡞⸆๣ࡢᢞ୚ィ⏬ࡀ⾜ࢃࢀࡿ࡞࡝ , ⸆≀἞⒪ࡢ㉁

ࡢྥୖࡀᅗࡽࢀ࡚࠸ࡿ . ࡉࡽ࡟ TDM ࡟ࡼࡗ࡚ᚓࡽࢀࡓࢹ࣮ࢱࡢ⵳✚࡜ , ࡑࢀࡽࡢゎᯒ⤖

ᯝ࡟ࡼࡗ࡚ྜ⌮ⓗ࡞⸆≀἞⒪ἲࡀ◊✲ࡉࢀ࡚࠸ࡿ . ≉࡟ᢠ MRSA ( ࣓ࢳࢩࣜࣥ⪏ᛶ㯤Ⰽࣈ

ࢻ࢘⌫⳦ , Methicillin-resistant Staphylococcus aureus) ⸆ࢆࡣࡌࡵ࡜ࡍࡿᢠ⳦⸆࡛ࡣ , ἞⒪ࡢ ᡂຌࡸ౑⏝ࡍࡿᢠ⳦⸆࡟ᑐࡍࡿ⣽⳦ࡢ⪏ᛶ໬ண㜵ࢆ┠ⓗ࡜ࡋ࡚ , ⸆≀ືែᏛ / ⸆ຊᏛ (pharmacokinetics/pharmacodynamics: PK/PD) ࡢ◊✲ࡀࡉ࠿ࢇ࡟⾜ࢃࢀ࡚࠸ࡿ .

ࡍ࡞ࢃࡕ , PD ࡜࡞ࡿ⣽⳦ࡢ᭱ᑠⓎ⫱㜼Ṇ⃰ᗘ (minimal inhibitory concentration: MIC) ࡟ᑐࡋ࡚ᚲせ࡞

἞⒪ᇦ⃰ᗘ࠶ࡿ࠸ࡣ⾑୰⃰ᗘ - ᫬㛫᭤⥺ୗ㠃✚ (area under the blood concentration-time curve:

AUC) ࢆ☜ಖࡍࡿࡓࡵ࡟ PK ⌮ㄽ࡟ᇶ࡙࠸ࡓᢞ୚ィ⏬ࡢ❧᱌࡜ᐇ㊶ࡀ࡞ࡉࢀ࡚࠸ࡿ .

⮫ᗋ࡛ࡣ⭾኱࡞✀㢮ࡢ⸆≀ࡀ౑ࢃࢀ࡚࠸ࡿࡀ , TDM ࡣ඲࡚ࡢ⸆≀࡟ࡘ࠸࡚ᚲせ࡜ࡉࢀ

ࡿࡶࡢ࡛ࡣ࡞࠸ . ᮏ㑥࡟࠾࠸࡚⌧ᅾ , TDM ࡢࡶ࡜࡟἞⒪ࡍࡿࡇ࡜ࡀಖ㝤࡜ࡋ࡚ㄆࡵࡽࢀ࡚

࠸ࡿ≉ᐃ⸆๣἞⒪⟶⌮ᩱࡢᑐ㇟⸆≀ࡣ , Table 1 ࡟♧ࡍࡶࡢ࡟␃ࡲࡗ࡚࠸ࡿ .

ࡇࢀࡽࡣ᭱

2

㐺἞⒪ᇦ⃰ᗘ࡜๪స⏝Ⓨ⌧⃰ᗘࡀ㏆ࡃ , (1) ⸆⌮཯ᛂࡀྍ㏫ⓗ࡛࠶ࡿࡇ࡜ , (2) ⸆⌮ຠᯝ࡜

యᾮ୰⃰ᗘ , ≉࡟⾑୰⃰ᗘ࡜ࡢ㛵ಀࡀ࠶ࡿ⛬ᗘ᫂ࡽ࠿࡟ࡉࢀ࡚࠸ࡿࡇ࡜ , (3) ⸆≀ཷᐜయ

㏆ഐ࡛ࡢ⸆⌮Ꮫⓗ࡞⪏ᛶࡀ㉳ࡇࡾ࡟ࡃ࠸ࡇ࡜ , (4) యᾮ୰⃰ᗘࡢᐃ㔞ἲࡀ☜❧ࡉࢀ࡚࠸ࡿ

ࡇ࡜ , (5) άᛶ௦ㅰ≀ࡢᏑᅾࡢ᭷↓ࡀ᫂ࡽ࠿࡟ࡉࢀ࡚࠸ࡿࡇ࡜ , (6) ⮫ᗋⓗ࡞⸆ືᏛⓗࢹ

࣮ࢱࡢ⵳✚ࡀ࠶ࡿࡇ࡜ , ࡜࠸ࡗࡓ᮲௳࡟࠶࡚ࡣࡲࡿ⸆≀⩌࡛࠶ࡾ , ࡇࡢࡼ࠺࡞⸆≀ࢆ⏝࠸

ࡿሙྜ࡟ TDM ࡣᏳ඲࡛ຠᯝⓗ࡞⸆≀⒪ἲࡢ㔜せ࡞ࢶ࣮ࣝ࡜࡞ࡿ . ࡉࡽ࡟⮫ᗋ࡛ࡣᵝࠎ࡞

せᅉࡀ⸆≀ࡢຠᯝ࡟ᙳ㡪ࢆཬࡰࡍࡀ , ≉࡟ (1) స⏝ࢆ┤᥋ホ౯ࡋ࡟ࡃ࠸⸆≀ , (2) ἞⒪ᇦ⃰

ᗘࡀ⊃࠸⸆≀ , (3) యෆືែࡢಶேᕪࡀ኱ࡁ࠸⸆≀ , (4) యෆືែ࡟㠀⥺ᙧᛶࡢ࠶ࡿ⸆≀ , (5)

⫢⮚ࡸ⭈⮚࡞࡝࡟㞀ᐖࡀ࠶ࡿᝈ⪅ࡸᝈඣ , 㧗㱋⪅࡛ᢞ୚㔞ࢆỴࡵ࡟ࡃ࠸⸆≀ , (6) ⸆≀ే⏝

࡟ࡼࡾ⸆≀̿⸆≀㛫┦஫స⏝ࢆ⏕ࡌࡿ࠾ࡑࢀࡀ࠶ࡿ⸆≀࡟ TDM ࡣ≉࡟᭷⏝ᛶࢆⓎ᥹ࡍ

ࡿ . ࡲࡓ , ᝈ⪅ࡀ᭹⏝ᣦ♧ࢆᏲࡗ࡚࠸࡞࠸ , ࡲࡓࡣㄗ⸆ࡢ␲࠸ࡢ࠶ࡿ㝿࡟ࡶ⏝࠸ࡽࢀࡿ . ࡉ

ࡽ࡟ , ⸆≀἞⒪ࡢ㐍Ṍ࡜࡜ࡶ࡟ᑐ㇟⸆≀ࡢࢽ࣮ࢬࡶኚ໬ࡋ࡚࠾ࡾ , ⦆࿴་⒪࡟࠾ࡅࡿ㙠③

⿵ຓ⸆࡜ࡋ࡚ࡢᢠ࡚ࢇ࠿ࢇ⸆㸦࢞ࣂ࣌ࣥࢳࣥ࡞࡝㸧ࡸ , ⭺ཎ⑓἞⒪࡟࠾ࡅࡿච␿ᢚไ⸆㸦ࢱ ࢡ࣒ࣟࣜࢫ࡞࡝㸧࡞࡝ , ᪤Ꮡࡢ TDM ᑐ㇟⸆≀࡟ࡘ࠸࡚ࡶࡑࡢᙺ๭࡟ᛂࡌࡓ᭱㐺἞⒪⃰ᗘ ࡀ᪂ࡓ࡟タᐃࡉࢀ࡚࠸ࡿ .

⾑୰⸆≀⃰ᗘ ᐃἲࡣ , ୺࡟ศ㞳ศᯒἲ࡜ච␿Ꮫⓗ ᐃἲ㸦࢖࣒ࣀ࢔ࢵࢭ࢖㸧࡟ศ㢮ࡉ

ࢀࡿ . ⑓㝔⸆๣㒊࡟࠾ࡅࡿ࣮ࣝࢳࣥᴗົ࡜ࡋ࡚ࡢ TDM ࡟࠾ࡅࡿᐃ㔞ࡣ࡯࡜ࢇ࡝࢖࣒ࣀ࢔

ࢵࢭ࢖ , ≉࡟⮬ື໬ࡉࢀࡓ⺯ග೫ග࢖࣒ࣀ࢔ࢵࢭ࢖ (fluorescence polarization immunoassay:

FPIA) ࡟ࡼࡗ࡚⾜ࢃࢀ࡚ࡁࡓ . ㏆ᖺࡣྠᵝࡢ࢖࣒ࣀ࢔ࢵࢭ࢖ἲࢆᦚ㍕ࡋࡓỗ⏝ᶵࡢ㛤Ⓨࡀ

㐍ࡳ , ⾑୰⸆≀⃰ᗘ ᐃᴗົࡣ᳨ᰝᐊ࠶ࡿ࠸ࡣእ㒊ጤク࡬࡜⛣⾜ࡋࡘࡘ࠶ࡿ . ࡑࡢࡼ࠺࡞

୰࡛ࡶ , ᪂つࡢ⸆๣ࡸ἞⒪ἲࢆᏳ඲࠿ࡘ᭷ຠ࡟฼⏝ࡍࡿࡓࡵ࡟ Table 1 ࡟♧ࡋࡓ TDM ᑐ

㇟⸆≀௨እࡢ⸆≀࡟ࡘ࠸࡚⾑୰⸆≀⃰ᗘࢆ ᐃࡍࡿሙྜࡀ࠶ࡿ . ࡋ࠿ࡋ࢖࣒ࣀ࢔ࢵࢭ࢖࡛

ࡣ᪂ࡓ࡟ᢠయసᡂࡀᚲせ࡛࠶ࡾ , ࢥࢫࢺࡀ㧗ࡃ , ỗ⏝ᛶࡀஈࡋ࠸ . ࡑࡢࡓࡵ , TDM ᑐ㇟⸆

௨እࡢ⸆≀࡟ࡘ࠸࡚ࡣศ㞳ศᯒἲࡀ⏝࠸ࡽࢀࡿ . ≉࡟㧗㏿ᾮయࢡ࣐ࣟࢺࢢࣛࣇ࢕࣮

(high-performance liquid chromatography: HPLC) ࡣ⡆౽࠿ࡘపࢥࢫࢺ࡛࠶ࡿࡇ࡜࠿ࡽ᭱ࡶ฼

⏝ࡉࢀࡿ ᐃᶵჾ࡛࠶ࡿ .

3

Table 1. Drugs Required Monitoring a Concentration in Plasma for Therapy

ᢠ୙ᩚ⬦⸆ࡢ࣋ࣉࣜࢪࣝ (Fig. 1) ࡣ 1980 ᖺ௦࡟ࣇࣛࣥࢫ࡛㛤Ⓨࡉࢀ , ᚰ➽᱾ሰࡸ୙ᩚ

⬦ࡢ἞⒪࡟౑⏝ࡉࢀ࡚ࡁࡓ⸆≀࡛࠶ࡿࡀ , ᪂つࡢ - ࣈࣟࢵ࣮࢝ࡸ࢝ࣝࢩ࣒࢘ᣕᢠ⸆ࡢⓏሙ

࡟క࠺἞⒪ᡓ␎ࡢኚ໬࡟ࡼࡾ , ࡇࢀࡽࡢ⑌ᝈ࡟ᑐࡍࡿ౑⏝㢖ᗘࡣῶᑡࡋ࡚࠸ࡿ . ࡋ࠿ࡋ㏆

ᖺ , ᚰᡣ⣽ື (atrial fibrillation: Af) ࡟ᑐࡍࡿ἞⒪ຠᯝࡀぢ┤ࡉࢀ , ෌ࡧ౑⏝㢖ᗘࡣ㧗ࡃ࡞

ࡾࡘࡘ࠶ࡿ .

Af ࡜ࡣ , ᚰ⮚ୖᐊࡢᵝࠎ࡞㒊఩࡛ᩓⓎⓗ࡟่⃭ఏᑟ⯆ዧࡢ࢚ࣜࣥࢺ࣮ࣜࡀⓎ⏕ࡋ , ṇᖖ

࡞ᚊືᛶ཰⦰࡟ࡼࡿᚰ⮚ࡢᢿฟᶵ⬟ࡀ␗ᖖࢆࡁࡓࡋ࡚➽ቨࡢᛴ㏿࡛୙つ๎࡞ᨥ⦰ࢆᘬࡁ㉳

ࡇࡍᚰ⑌ᝈࡢ୍ࡘ࡛࠶ࡿ . Af ࡣ⮬ぬ⑕≧࡟ஈࡋ࠸ሙྜࡶከ࠸ࡶࡢࡢ , ⬻᱾ሰⓎ⑕ࡢ⊂❧ࡋ ࡓ༴㝤ᅉᏊ࡜ࡋ࡚ᣲࡆࡽࢀ࡚࠾ࡾ ,

㔜⑕ࡢሙྜࡣṚ࡟⮳ࡿྍ⬟ᛶࡀ࠶ࡿ . Framingham ◊

✲

࡟࠾࠸࡚ , Af ࡢⓎ⑕ᅉᏊ࡟ࡣຍ㱋 , ⢾ᒀ⑓ , 㧗⾑ᅽ⑕ , ᚰ➽᱾ሰ࠾ࡼࡧᚰ୙඲ࡢ᪤ 

࡞࡝ࡀᣲࡆࡽࢀ࡚࠸ࡿࡀ , ᇶ♏⑌ᝈࡢ᭷↓ࢆ㝖እࡋࡓሙྜ࡛ࡶຍ㱋࡟క࠸ᛴ⃭࡟Ⓨ⑕⋡ࡀ

ୖ᪼ࡍࡿ࡜ࡉࢀ࡚࠸ࡿ . ࢃࡀᅜ࡟࠾࠸࡚ࡣ , ⏨ᛶ࡛ࡣ 40 ṓ௦ࡢ Af Ⓨ⑕⋡ࡀ⣙ 1% ࡛࠶

ࡗࡓࡢ࡟ᑐࡋ , 80 ṓ௦࡛ࡣ⣙ 15% ࡜㢧ⴭ࡟ቑຍࡋ࡚࠾ࡾ ,

ᅜෆእࢆၥࢃࡎ⤒ᖺⓗ࡟ Af

Classification Drugs

Digitalis and preparations digitalis, digitoxin

Theophylline and preparations theophylline, aminophylline

Antiarrhythmic drugs procainamide, N-acetylprocainamide, aprindine, disopyramide, lidocaine, pilsicainide, propafenone,

mexiletine, flecainide, quinidine, cibenzoline, amiodarone, pirmenol, bepridil, sotalol

Antiepileptic drug phenobarbital, nitrazepam, primidone, diazepam, phenytoin, carbamazepine, zonisamide, ethosuximide, acetazolamide, sodium valproate, trimethadione, clonazepam, clobazam, sultiame

Antibiotics gentamicin, amikacin, streptomycin, tobramycin, arbekacin, teicoplanin, vancomycin, voliconazole

Immunosuppressive cyclosporine, mycophenolate mofetil, tacrolimus, everolimus

Salicylic acid salicylic acid

Antitumor agents imatinib, methotrexate

Haloperidol and bromperidol haroperidol, bromperidol

Lithium lithium carbonate

4

ࡢ᭷⑓⋡ࡣቑຍࡋ࡚࠸ࡿ .

Fig. 1. Chemical Structure of Bepridil Hydrochloride.

Af ࡟ᑐࡋ࡚ࡣ , ᚰᡣ⣽ືⓎ⏕ࡢࢺ࣮ࣜ࢞࡜࡞ࡿᮇእ཰⦰ࡢⓎ⏕㒊఩ࢆ↝ⅎࡋ࡚ , ᚰ➽ࡢ

␗ᖖ⯆ዧࢆᚰᡣ࠿ࡽ㟁Ẽⓗ࡟㝸㞳ࡍࡿእ⛉ⓗฎ⨨㸦࢝ࢸ࣮ࢸࣝ࢔ࣈ࣮ࣞࢩࣙࣥ἞⒪㸧ࡀ᰿

἞⒪ἲ࡜ࡋ࡚⾜ࢃࢀ࡚࠸ࡿ . ࡲࡓ , ሙྜ࡟ࡼࡗ࡚ࡣ࣮࣌ࢫ࣓࣮࣮࢝ᇙࡵ㎸ࡳࡀ㑅ᢥࡉࢀࡿ

ࡀ , ṇᖖ࡞ᚊື໬㸫Ὕㄪᚊ໬࡟ࡣ⿵ຓⓗ࡞⸆≀⒪ἲࡀ୙ྍḞ࡛࠶ࡾ , እ⛉ⓗฎ⨨࡟ࡼࡿ἞

⒪ࡀ୙㐺ᛂ࡞ሙྜࡸฎ⨨ᚋࡢ෌Ⓨ౛࡟ࡣ , ⸆≀⒪ἲࡀ୰ᚰ࡜࡞ࡿ .

Ὕㄪᚊ (sinus

rhythm 㸸 SR) ࢆ⥔ᣢࡍࡿࡓࡵ࡟ࡣ Af ࡢཎᅉ࡜ࡉࢀ࡚࠸ࡿ࢚ࣜࣥࢺ࣮ࣜࢆᾘኻࡉࡏࡿࡇ࡜

ࡀ᭷ຠ࡛࠶ࡾ , ᚰ➽⣽⬊㛫ࡢ่⃭ఏᑟࢆ㐜ᘏࡉࡏࡿࡇ࡜ࡸ᭷ຠ୙ᛂᮇࢆᘏ㛗ࡉࡏࡿࡇ࡜ࡀ SR ࡬ࡢ㌿໬࠾ࡼࡧ⥔ᣢࢆಁࡍ࡜⪃࠼ࡽࢀ࡚࠸ࡿ . ࡇࡢࡓࡵ , SR ⥔ᣢ἞⒪࡟࠾࠸࡚౑⏝ࡉ

ࢀࡿ⸆๣࡜ࡋ࡚ , Na

ࢳࣕࢿࣝࢆ㐽᩿ࡋ่࡚⃭ఏᑟ㐜ᘏࢆಁࡍ Vaugham-Williams ศ㢮ࡢ

➨ I ⩌⸆㸦ࢪࢯࣆ࣑ࣛࢻ , ࣆ࣓ࣝࣀ࣮ࣝ࡞࡝㸧ࡸ , K

ࢳࣕࢿࣝ㐽᩿࡟ࡼࡾᚰ⮚ࡢ᭷ຠ୙ᛂ ᮇࢆᘏ㛗ࡉࡏࡿస⏝ࢆ୺࡜ࡍࡿ➨ III ⩌⸆㸦࢔࣑࢜ࢲࣟࣥ , ࢯࢱ࣮ࣟࣝ࡞࡝㸧ࡀ⏝࠸ࡽࢀ

ࡿ . ㏆ᖺࡣࡇࢀࡽ࡟࣐ࣝࢳࢳࣕࢿࣝࣈࣟࢵ࣮࡛࢝࠶ࡿ࣋ࣉࣜࢪࣝࡀຍࢃࡗࡓ .

2005 ᖺࡼࡾᮏ㑥࡟࠾࠸࡚་ᖌ୺ᑟ἞㦂࡜ࡋ࡚⾜ࢃࢀࡓࠕᣢ⥆ᛶᚰᡣ⣽ື೵Ṇ㝆ୗ࠾ࡼࡧ

ࡑࡢ⏝㔞཯ᛂᛶ㸦ࣉࣛࢭ࣎ᑐ↷஧㔜┣᳨ẚ㍑ヨ㦂㸧㸸 J-BAF Study ࠖ

࡟࠾࠸࡚ , ࣋ࣉࣜࢪ

ࣝᢞ୚⩌࡟࠾ࡅࡿὝㄪᚊ໬ࡀࣉࣛࢭ࣎⩌࡟ẚ࡭࡚᭷ព࡟຾ࡿ἞⒪ᡂ⦼ࢆ♧ࡋࡓࡇ࡜࠿ࡽ ,

࣋ࣉࣜࢪࣝ࡟ࡣ 2008 ᖺ࡟ᣢ⥆ᛶᚰᡣ⣽ື࡟ᑐࡍࡿ㐺ᛂࡀ㏣ຍࡉࢀࡓ . ୍᪉࡛࣋ࣉࣜࢪࣝ

ࡣ㔜⠜࡞๪స⏝ࢆⓎ⌧ࡍࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠾ࡾ , ᚰ㟁ᅗୖ , ⏝㔞౫Ꮡⓗ࡟ QT 㛫㝸ࢆᘏ㛗ࡉ CH

CH

CH

CH

CH

CH

CH

CH O

N

N 䞉 HC 䡈

5

ࡏ , 㔜⠜࡞ሙྜ࡟ࡣ torsades de pointes (TdP) ࢆㄏⓎࡍࡿ༴㝤ᛶࡀᣦ᦬ࡉࢀ ,

2012 ᖺ࡟≉

ᐃ⸆๣἞⒪⟶⌮ᩱࡢᑐ㇟⸆๣࡟࡞ࡗ࡚࠸ࡿ . ࡋ࠿ࡋ , ᾏእ࡟࠾࠸࡚ Af ࡢ⸆≀἞⒪ࡣᢠจ ᅛ⒪ἲࢆ୰ᚰ࡜ࡋ࡚࠾ࡾ , Ὕㄪᚊ⥔ᣢ࡟ᑐࡋ࡚ࡣ࢔࣑࢜ࢲࣟࣥࡀ㑅ᢥࡉࢀࡿሙྜࡀከ࠸ . ࡑࡢࡓࡵ࣋ࣉࣜࢪࣝࡢ౑⏝ࡣ᪥ᮏ࡟㝈ࡽࢀ࡚࠾ࡾ , ᭷ຠᛶࡸ๪స⏝࡟㛵ࡍࡿሗ࿌ࡣᑡ࡞࠸ . ୍᪉ , ㏆ᖺࡢ໬Ꮫ⒪ἲࡸ㧗ᗘ་⒪ᢏ⾡ࡢ㐍Ṍ࡟క࠺᫆ឤᰁᝈ⪅ࡢቑຍ࡟ࡼࡾ , ឤᰁ⑕἞

⒪࡟࠾࠸࡚ࡣ MRSA ឤᰁ⑕௨እ࡟ࡶ , ከ๣⪏ᛶ⥳⮋⳦ (multi-drug resistant Pseudomonas aeruginosa: MDRP), ᇶ㉁≉␗ᛶᣑᙇᆺ - ࣛࢡࢱ࣐࣮ࢮ (extended-spectrum

ESBL) ⏘⏕⳦࡞࡝ࡢከ๣⪏ᛶ⳦ࡸ┿⳦࡟ࡼࡿ⑓㝔ឤᰁࡀၥ㢟࡜࡞ࡗ࡚࠸ࡿ . ┿⳦⑕࡟ᑐࡋ

࡚ࡣ㏆ᖺ࣑࢝ࣇ࢓ࣥࢠࣥ , ࢝ࢫ࣏ࣇ࢓ࣥࢠࣥ , ࣎ࣜࢥࢼࢰ࣮ࣝ࡞࡝ࡢ᪂つᢠ┿⳦⸆ࡸ࣏ࣜ

ࢯ࣮࣐ࣝ࢔࣒࣍ࢸࣜࢩࣥ B ࡜࠸ࡗࡓ᪤Ꮡࡢᢠ┿⳦⸆ࢆ〇๣Ꮫⓗ࡟ᨵኚࡋࡓ⸆๣ࡀୖᕷࡉ

ࢀ࡚࠸ࡿ . ࣑࢝ࣇ࢓ࣥࢠࣥࡣ┿⳦࡟≉␗ⓗ࡞⣽⬊ቨࡢ୺せᵓᡂᡂศ࡛࠶ࡿ 1, 3-E-D- ࢢࣝ࢝

ࣥࡢ⏕ྜᡂࢆ㜼ᐖࡍࡿࡇ࡜࡟ࡼࡾ , Candida ᒓ࡟ᑐࡋ࡚ẅ⳦ⓗ࡟స⏝ࡍࡿ࢟ࣕࣥࢹ࢕ࣥ⣔

ᢠ┿⳦⸆࡛࠶ࡿ .

࣑࢝ࣇ࢓ࣥࢠࣥ (Fig. 2) ࡣ᪤Ꮡࡢᢠ┿⳦⸆࡜ẚ㍑ࡋ࡚๪స⏝ࡸ⸆≀

┦஫స⏝ࡀᑡ࡞࠸ࡇ࡜࠿ࡽ , ᮏ㑥࡟࠾࠸࡚ࡣ࢝ࣥࢪࢲ⾑⑕ࡸ᧛✀ᛶ࢝ࣥࢪࢲ⑕࡞࡝ࡢ῝ᅾ ᛶ┿⳦⑕࡟ᑐࡋ࡚➨ 1 㑅ᢥ⸆࡜ࡋ࡚᥎ዡࡉࢀ࡚࠸ࡿࡀ ,

ᢠ MRSA ⸆ࡸ௚ࡢᢠ┿⳦⸆࡜

ẚ㍑ࡋ࡚ PK/PD ࡟㛵㐃ࡍࡿ᝟ሗࡣᑡ࡞࠸ . ┿⳦ឤᰁ⑕࡟ᑐࡍࡿᢠ┿⳦⸆ࡢ PK/PD ࡟ࡘ

࠸࡚ࡣ in vitro ࡛ࡢᢠ┿⳦άᛶࡀ in vivo ࡢ⤖ᯝ࡜ᚲࡎࡋࡶ┦㛵ࡏࡎ ,

ࡲࡓᐇ㦂࡟㐺ࡋ

ࡓື≀ࣔࢹࣝࡀᑡ࡞࠸ࡇ࡜࠿ࡽࡶ༑ศ࡞᳨ウࡣ⾜ࢃࢀ࡚࠸࡞࠸ . ୍᪉ , ᪂つ࢔ࢰ࣮ࣝ⣔ᢠ

┿⳦⸆࡛࠶ࡿ࣎ࣜࢥࢼࢰ࣮ࣝࡣ , ᩓぢࡉࢀࡿ⾑୰⸆≀⃰ᗘ࡜᭷ຠᛶ࠶ࡿ࠸ࡣ๪స⏝Ⓨ⌧ࡢ

ሗ࿌

ࢆࡶ࡜࡟┠Ᏻ࡜࡞ࡿ㜈್ࢆタᐃࡋ , ≉ᐃ⸆๣἞⒪⟶⌮ᩱࡢᑐ㇟⸆≀࡜ࡋ࡚⮫ᗋ࡛

⏝࠸ࡽࢀ࡚࠸ࡿ . ┿⳦ឤᰁ⑕࡟ࡘ࠸࡚ࡣ㏆ᖺ , ᢠ┿⳦⸆ࡢ౑⏝㢖ᗘቑຍ࡟కࡗ࡚⸆๣⪏ᛶ

┿⳦ࡢฟ⌧ࡀၥ㢟࡜࡞ࡗ࡚࠸ࡿ .

⌧ᅾ , ᢠ┿⳦๣࡟ᑐࡍࡿ⪏ᛶ໬ࡢᗈࡀࡾࡣᢠ⳦⸆࡯

࡝࡛ࡣ࡞࠸ . ࡋ࠿ࡋ , ᢠ⳦⸆࡜ྠᵝ࡟⪃࠼ࡓሙྜ , ┿⳦ឤᰁ⑕࡟ᑐࡍࡿ⸆≀἞⒪ࡣ㛗ᮇ࡟

ࢃࡓࡿ⑕౛ࡶࡲࢀ࡛ࡣ࡞ࡃ , ౑⏝㢖ᗘࡢ㧗ࡉࡸప࠸⾑୰⃰ᗘ࡛ࡢ౑⏝ᮇ㛫ࡢ㛗ࡉࡀ⪏ᛶ໬

ࢆຓ㛗ࡍࡿࡶࡢ࡜᥎ ࡉࢀࡿ . PK/PD ⌮ㄽ࡟ࡶ࡜࡙࠸ࡓຠᯝⓗ࡞ᢠ┿⳦⸆ࡢᢞ୚ࡣ┿⳦࡟

ᑐࡍࡿᢠ┿⳦⸆ࡢឤཷᛶࡢ⥔ᣢ࡟ࡘ࡞ࡀࡿ . ࡑࡇ࡛ , ๓㏙ࡋࡓࡼ࠺࡟๪స⏝ࡸ௚๣࡜ࡢ⸆

6

≀┦஫స⏝ࡀᑡ࡞࠸ࡇ࡜࠿ࡽ౑⏝㢖ᗘࡀ㧗ࡃ࡞ࡗ࡚࠸ࡿ࣑࢝ࣇ࢓ࣥࢠࣥ࡟ὀ┠ࡋ , TDM

◊✲ࡢᑐ㇟࡜ࡋࡓ .

ࡇࡢࡼ࠺࡟ , ࡑࡢ⮫ᗋຠᯝ࡜⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ࠶ࡿ࠸ࡣ࣑࢝ࣇ࢓ࣥࢠࣥ⃰ᗘࡢ㛵ಀ ࡣ᫂☜࡛ࡣ࡞ࡃ , ࡇࢀࡽࢆ⏝࠸ࡓ἞⒪࡟࠶ࡓࡗ࡚ࡣ᭷ຠ⾑୰⃰ᗘᇦ࡞࡝ࡢᣦᶆࡢᚲせᛶࡀ 㧗࠸ . ࡑࡇ࡛ᮏ◊✲࡛ࡣ࣋ࣉࣜࢪࣝ࠾ࡼࡧ࣑࢝ࣇ࢓ࣥࢠࣥࡢ⡆౽࡞⾑₢୰⃰ᗘ ᐃἲࡢ☜

❧࡜ , ᭷ຠᛶ࡜⾑୰⃰ᗘࡢ㛵ಀࢆ᫂ࡽ࠿࡟ࡍࡿࡇ࡜ , ࠾ࡼࡧ TDM ࢆ⾜࠺ࡇ࡜ࡢ᭷⏝ᛶࢆ

ホ౯ࡍࡿࡇ࡜ࢆ┠ⓗ࡜ࡋࡓ .

Fig. 2. Chemical Structure of Micafungin Sodium.

O OH

OH

O O O

O O

O

O

O O H

H

H H

H

H

H H H H

H H

H H

H

N

NH N

NH H

N NH

HO

OH OH N

OH HO

HO OH

HN CH₃

H₃C H2N

SO₃Na

O H3C

7

➨ 1 ❶ ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲࡢᵓ⠏

➨ 1 ⠇ ⥴ゝ

ᗎㄽ࡛㏙࡭ࡓࡼ࠺࡟ , ࣋ࣉࣜࢪࣝࡢ᭷ຠᛶ࠾ࡼࡧ๪స⏝ࡣ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ౫Ꮡⓗ

࡟Ⓨ⌧ࡍࡿ࡜⪃࠼ࡽࢀ࡚࠸ࡿࡶࡢࡢ ,

ࡇࢀࡽࡢ㛵ಀࢆ᫂☜࡟ࡋࡓሗ࿌ࡣ࡞࠸ . ᡃࠎࡣࡑ ࡢ㛵ಀࢆ᫂ࡽ࠿࡟ࡍࡿࡇ࡜ࢆ┠ⓗ࡜ࡋ࡚ , ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ࡜⮫ᗋຠᯝ࡜ࡢ㛵ಀ࡟ࡘ

࠸᳨࡚ウࢆ⾜࠺ࡇ࡜࡜ࡋࡓ . ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ 1980 ᖺ௦ᚋ༙ࡲ࡛࢞ࢫࢡ࣐ࣟࢺࢢ

ࣛࣇ࢕࣮࡟ࡼࡾ ᐃࡉࢀ࡚࠸ࡓࡀ ,

ࡑࡢᚋ , Ng ࡽ

ࡸ Taguchi ࡽ

࡟ࡼࡾ , HPLC ࢆ

⏝࠸ࡓ᪉ἲࡀሗ࿌ࡉࢀࡓ . ࡋ࠿ࡋ , ᙼࡽࡢ౑⏝ࡍࡿෆᶆ‽≀㉁ (internal standard: IS) ࡣ〇

⸆௻ᴗ࠿ࡽࡢ౪୚ࢆᚲせ࡜ࡍࡿࡇ࡜࠿ࡽ , ⮫ᗋᛂ⏝ࡍࡿ᪉ἲ࡜ࡋ࡚ࡣ⡆౽࡞ࡶࡢ࡛ࡣ࡞࠸ .

ࡲࡓ , ࣋ࣉࣜࢪࣝࡀ⏝࠸ࡽࢀࡿᚠ⎔ჾ⑌ᝈ἞⒪㡿ᇦ࡛ࡣ⸆≀἞⒪ࡀ୰ᚰ࡜࡞ࡾ , ⾑₢୰࡟

Ꮡᅾࡍࡿᵝࠎ࡞⸆≀ࡀᐃ㔞ࢆጉᐖࡍࡿྍ⬟ᛶࡣ㧗࠸ . ࡑࡢࡓࡵᮏ❶࡛ࡣ , ẚ㍑ⓗධᡭࡋࡸ

ࡍ࠸ヨ⸆ࢆ IS ࡜ࡋ࡚౑⏝ࡋ , ࡉࡲࡊࡲ࡞ే⏝⸆ࡀᢞ୚ࡉࢀ࡚࠸ࡿᝈ⪅࡟࠾ࡅࡿ⾑₢୰࣋

ࣉࣜࢪࣝ⃰ᗘ ᐃἲࢆᵓ⠏ࡍࡿࡇ࡜ࢆ┠ⓗ࡜ࡋࡓ . ేࡏ࡚ ᐃ᮲௳࡟࠾ࡅࡿ᪥ෆ࠾ࡼࡧ᪥

ᕪ෌⌧ᛶ , ⾑₢ࢆ෾⤖ಖᏑࡋࡓሙྜࡢ⸆≀ࡢᏳᐃᛶ࡟ࡘ࠸᳨࡚ウࡋࡓ . ࡉࡽ࡟ , ⮫ᗋୖ࣋

ࣉࣜࢪࣝ࡜㧗㢖ᗘ࡟ే⏝ࡉࢀ࡚࠸ࡓ⸆≀࡟ࡼࡿᐃ㔞ጉᐖ࡟ࡘ࠸᳨࡚ウࡋࡓ .

➨ 2 ⠇ ᪉ἲ

➨ 1 㡯 ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ

1 㸧 ౑⏝⸆≀࠾ࡼࡧヨ⸆

࣋ࣉࣜࢪࣝሷ㓟ሷࡣ ALEXIS BIOCHEMICALS (New York, USA) ࡼࡾ , 1- ࢼࣇࢺ࣮ࣝ , ࢺ

࢚ࣜࢳࣝ࢔࣑ࣥ , ࣜࣥ㓟 , Ỉ㓟໬ࢼࢺ࣒ࣜ࢘ , ሷ㓟 , ࢔ࢭࢺࢽࢺࣜࣝ , ࢚ࢱࣀ࣮ࣝ , ࣓ࢱࣀ

࣮ࣝࡣ࿴ග⣧⸆ᕤᴗᰴᘧ఍♫ ( ኱㜰 ) ࡼࡾ㉎ධࡋࡓ . ඲࡚ࡢヨ⸆ࡣ≉⣭ࡲࡓࡣ HPLC ศᯒ

8

⏝ࢆ౑⏝ࡋࡓ .

2 㸧 ᳨య᥇⾑࠾ࡼࡧ⾑₢ฎ⌮

ࣈࣛࣥࢡ⏝ࡢ⾑ᾮࡣ࣊ࣃࣜࣥῧຍ᥇⾑⟶࡟ᅇ཰ࡋࡓ . ᚓࡽࢀࡓ⾑ᾮࡣ 25 Υ , 400 g ࡟࡚

20 ศ㛫㐲ᚰศ㞳ࡋ , ᚓࡽࢀࡓ⾑₢ࢆࣉࣛࢫࢳࢵࢡࢳ࣮ࣗࣈ࡟ศྲྀࡋࡓࡢࡕ , 㸫 20 Υ࡛ಖᏑ ࡋࡓ .

3 㸧 ࢧࣥࣉࣝㄪ〇

ࢧࣥࣉࣝㄪ〇ἲࢆ Chart 1 ࡟♧ࡋࡓ . 500 L ࣜࣥ㓟࣒࢝ࣜ࢘⦆⾪ᾮ (100 mM, pH 7.4),

500 L IS ⁐ᾮ㸦࢔ࢭࢺࢽࢺࣜࣝ࡟⁐ゎࡋࡓ 2.5 g/mL 1- ࢼࣇࢺ࣮ࣝ⁐ᾮ㸧 , 20 PL ࢔ࢭࢺࢽ

ࢺࣜࣝ࠶ࡿ࠸ࡣྛ⃰ᗘࡢ࣋ࣉࣜࢪࣝ⁐ᾮ㸦⁐፹㸸࢔ࢭࢺࢽࢺࣜࣝ㸧ࢆ⾑₢ 500 L ࡟ῧຍ ࡋࡓ . ࣋ࣉࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝࡣ , 2.5 mL ࡢ n- ࣊࢟ࢧࣥࢆຍ࠼᣺┞ᶵ (MULTI SHAKER MS-300, ASONE, ኱㜰 ) ࢆ⏝࠸࡚ 2,000 rpm, 10 ศ㛫᣺┞ࡍࡿࡇ࡜࡟ࡼࡾᢳฟࡋ ࡓ . 㐲ᚰᶵ (centrifuge 5702, Eppendorf, Hamburg, Germany) ࡛ᐊ ୗ , 1,000 g ࡟࡚Ỉᒙ࡜ n-

࣊࢟ࢧࣥᒙ࡟ศ㞳ࡋࡓᚋ , n- ࣊࢟ࢧࣥᒙࢆ࢞ࣛࢫヨ㦂⟶࡟ศྲྀࡋࡓ . ṧ´࡟ n- ࣊࢟ࢧࣥࢆ

2.5 mL ຍ࠼ , ෌ᗘᢳฟࡋࡓ . ᚓࡽࢀࡓ n- ࣊࢟ࢧࣥᒙ (5.0 mL) ࡣヨ㦂⟶⃰⦰ჾ (TC-8 concentrator, Taitec, ᇸ⋢ ) ࡟ࡼࡾ 37 Υ࡛⵨Ⓨ஝ᅛࡉࡏࡓ . ᚓࡽࢀࡓṧ´ࡣ 250 L ࡢ⛣ື

┦࡟⁐ゎࡋ࡚෌ᗘ㐲ᚰศ㞳ࡋࡓࡢࡕ , ୖΎ 50

ࢆ HPLC ࡢὀධヨᩱ࡜ࡋࡓ .

9

Chart 1. Procedure for Sample Preparation to Measure Bepridil in Human Plasma

4 㸧 HPLC ᮲௳

HPLC ࢩࢫࢸ࣒ (Shimadzu, ி㒔 ) ࡣ࣏ࣥࣉ࡜ࡋ࡚ LC-10A, ࣒࣮࢝ࣛ࢜ࣈࣥ࡜ࡋ࡚

CTO-10AS, ⣸እ㒊྾཰᳨ฟჾ࡜ࡋ࡚ SPD-10A ࢆ౑⏝ࡋ , ศᯒ࣒࢝ࣛ࡟ࡣ Inertsil C

-3 column (4.6 ™ 150 mm, 5.0 Pm particle size, GL Sciences, ᮾி ) ࢆ౑⏝ࡋࡓ . ࢹ࣮ࢱྲྀᚓ࡟ࡣ

࢖ࣥࢸࢢ࣮ࣞࢱ (C-R8A) ࢆ⏝࠸ࡓ . ⛣ື┦ࡣ㐣ཤ࡟ሗ࿌ࡉࢀ࡚࠸ࡿ⤌ᡂ

࡟ಟṇࢆ

ຍ࠼ , 50 mM ࣜࣥ㓟Ỉ⁐ᾮ (pH 3.0): ࣓ࢱࣀ࣮ࣝ : ࢔ࢭࢺࢽࢺࣜࣝ : ࢺ࢚ࣜࢳࣝ࢔࣑ࣥ

(57:3:40:1, v/v) ࡜ࡋࡓ . ࣒࢝ࣛ ᗘࡣ 55 Υ࡜ࡋ , ὶ㏿ࡣ 0.9 mL/min ࡟タᐃࡋࡓ . ᳨ฟἼ㛗 ࡣ 254 nm ࡜ࡋࡓ .

5 㸧 ⾑₢⏤᮶ᡂศࡢ ᐃ⣔࡬ࡢᖸ΅ࡢ☜ㄆ

⾑₢⏤᮶ࣆ࣮ࢡࡀ࣋ࣉࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝ⏤᮶ࣆ࣮ࢡ࡟ᖸ΅ࡋ࡞࠸ࡇ࡜ࡣ , ࣋ࣉ

ࣜࢪࣝᮍᢞ୚ࡢ␗࡞ࡿ 4 ྡࡢ⿕㦂⪅ࡼࡾ , ࡑࢀࡒࢀࡢྠពࡢୖ࡛ᥦ౪ࡉࢀࡓ⾑₢ࢆ⏝࠸

Shaken at 2,000 r.p.m. for 20 min and centrifuged, at 1,000 gfor 5 min Supp. was removed to another tube

100 mM KH₂PO₄(pH 7.4) 500 L 2.5 g/mL 1-naphthol 500 L

Acetonitril 500 L

Plasma 500 L

n-Hexane 2.5 mL

n-Hexane 2.5 mL

Supp. was removed to another tube

Evaporated to dryness 5.0 mL n-Hexane layer

Dissolved to mobile phase 250 L Centrifuged at 1,000 gfor 15 min

Shaken at 2,000 r.p.m. for 20 min and centrifuged, at 1,000 gfor 5 min

Supp. for HPLC Residue

10

࡚☜ㄆࡋࡓ .

6 㸧 ┤⥺ᛶ

᳨㔞⥺ࡣ 5 ⃰ᗘࡢᶆ‽࣋ࣉࣜࢪࣝ⁐ᾮ (25, 100, 250, 500, 1,000 ng/mL) ࢆ⏝࠸࡚ ᐃࡢ ࡘ࡝సᡂࡋࡓ . 1 ⃰ᗘࡈ࡜࡟ 500 L ࡢࣈࣛࣥࢡ⾑₢࡟ྛタᐃ⃰ᗘࡢ 25 ಸ࡟ㄪ〇ࡋࡓ࣋ࣉ

ࣜࢪࣝ⁐ᾮ㸦⁐፹㸸࢔ࢭࢺࢽࢺࣜࣝ㸧ࢆ 20

ࡎࡘῧຍࡋࡓ . ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ᭱

ᑠ஧஌ἲ࡟ࡼࡾᅇᖐ┤⥺ࢆ⟬ฟࡋ࡚௨ୗࡢᘧ࡟ࡼࡾồࡵࡓ .

Bepridil concentration (Pg/mL) = u x +

x ࡣ࣋ࣉࣜࢪࣝ /IS ࡢࣆ࣮ࢡ㠃✚ẚ , , ࢆࡑࢀࡒࢀᅇᖐ┤⥺࡟ࡼࡗ࡚ᚓࡽࢀࡓഴࡁ࠾ࡼ

ࡧ y ษ∦࡜ࡋࡓ .

7 㸧 ᳨ฟ㝈⏺࠾ࡼࡧᐃ㔞㝈⏺

ᶆ‽࣋ࣉࣜࢪࣝ⁐ᾮࢆ⏝࠸࡚సᡂࡋࡓ᳨㔞⥺ࢆ౑ࡗ࡚ , ᳨ฟ㝈⏺࠾ࡼࡧᐃ㔞㝈⏺ࢆỴᐃ ࡋࡓ . ࡍ࡞ࢃࡕ᳨ฟ㝈⏺ࡣᮏ ᐃἲ࡟᳨࡚ฟ࡛ࡁࡿ᭱ᑠ⃰ᗘ࡜ࡋ , ᐃ㔞㝈⏺ࡣ ᐃ᫬࡟チ ᐜ⠊ᅖࡢ⢭ᗘ࠾ࡼࡧ┿ᗘࢆᚓࡽࢀࡿ᭱ప⃰ᗘ࡜ࡋࡓ .

8 㸧  ᐃ⢭ᗘ

2.5, 250, 1,000 ng/mL ࡜࡞ࡿࡼ࠺࡟ᶆ‽࣋ࣉࣜࢪࣝ⁐ᾮࢆῧຍࡋࡓࣈࣛࣥࢡ⾑₢㸦࣋ࣉࣜ

ࢪࣝῧຍ⾑₢㸧ࢆ⏝࠸࡚ , ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃ࡟࠾ࡅࡿ᪥ෆ࠾ࡼࡧ᪥ᕪ෌⌧ᛶࡢ⢭

ᗘࢆồࡵࡓ .  ᐃ┿ᗘࡣ⃰ᗘ࠾ࡼࡧ⌮ㄽ್࡟ᑐࡍࡿ๭ྜ࡜ࡋ࡚⟬ฟࡋࡓ .  ᐃ⢭ᗘ (CV%) ࡣ࣋ࣉࣜࢪࣝῧຍ⾑₢ (2.5, 250, 1,000 ng/mL) ࢆ⏝࠸࡚ᚓࡽࢀࡓ⃰ᗘࡼࡾ , ኚືಀᩘ࡜ࡋ

࡚⟬ฟࡋࡓ .

11

9 㸧  ᐃ᮲௳࡟࠾ࡅࡿศ㞳ࡢ≉␗ᛶ

࣋ࣉࣜࢪࣝᢞ୚ᝈ⪅ࡢデ⒪㘓ࢆㄪᰝࡋ , ࣋ࣉࣜࢪࣝ࡜ే⏝㢖ᗘࡢ㧗࠿ࡗࡓ 32 ✀㢮ࡢ⸆

≀ࢆᢳฟࡋࡓ . ࡞࠾ , ᝈ⪅ࡽࡢẶྡ , ᝈ⪅␒ྕ࡞࡝ࡣ༏ྡ໬ࡋ࡚ྲྀࡾᢅࡗࡓ . ࡇࢀࡽࡢ⸆≀

(Table 2) ࢆᑐ㇟࡟ , HPLC ࡟࠾ࡅࡿ࣋ࣉࣜࢪࣝ࡜ 1- ࢼࣇࢺ࣮ࣝ⏤᮶ࣆ࣮ࢡ࡬ࡢᖸ΅ࡢ᭷↓

ࢆ᳨ウࡋࡓ . ᑐ㇟⸆≀ࡣࡑࢀࡒࢀࡢ᝿ᐃࡉࢀࡿ᭱㧗⾑୰⃰ᗘ࡟ᑐᛂࡋࡓ⃰ᗘ࡜࡞ࡿࡼ࠺࡟

⛣ື┦࡟⁐ゎࡋࡓࡢࡕ , HPLC ࡬ὀධࡋࡓ . ࣋ࣉࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝ⏤᮶ࣆ࣮ࢡࡢ

㏆ഐ࡟ࣆ࣮ࢡࡀᚓࡽࢀࡓ⸆≀࡟ࡘ࠸࡚ࡣ 500 L ࡢ 100 mM ࣜࣥ㓟࣒࢝ࣜ࢘⦆⾪ᾮ (pH

7.4), 500 L ࢔ࢭࢺࢽࢺࣜࣝ , 500 L ࣈࣛࣥࢡ⾑₢ࢆຍ࠼ࡓᚋ , n- ࣊࢟ࢧࣥ࡟ࡼࡾᢳฟࡋࡓ .

ᢳฟࡢᑐ㇟࡜࡞ࡗࡓ⸆≀ࡣ 5 ✀㢮࡛࠶ࡗࡓ .

10 㸧 ⾑₢ヨᩱࡢಖᏑ᮲௳ࡢጇᙜᛶ

࡟࡚ 42 ᪥㛫ࡲ࡛ಖ⟶ࡋࡓሙྜࡢ⾑₢୰ࡢ࣋ࣉࣜࢪࣝࡢᏳᐃᛶࢆ , 2.5, 250, 1,000

ng/mL ࡟࠾࠸᳨࡚ウࡋࡓ . ࣋ࣉࣜࢪࣝ⃰ᗘࡢపୗ⋡ࡣᙜ᪥ㄪ〇ࡋࡓ㠀෭෾࣋ࣉࣜࢪࣝῧຍ

⾑₢࡜ẚ㍑ࡍࡿࡇ࡜࡟ࡼࡾ⟬ฟࡋࡓ .

11 㸧 ⤫ィฎ⌮

⤖ᯝࡣࡍ࡭࡚ᖹᆒ್sᶆ‽೫ᕪ (mean s S.D.) ࡛⾲ࡋࡓ .

➨ 2 㡯 ⮫ᗋᝈ⪅࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃ

1 㸧 ᑐ㇟ᝈ⪅

◊✲ࣉࣟࢺࢥࣝࡣᕷ❧ᮐᖠ⑓㝔೔⌮ጤဨ఍ࡢᢎㄆࡢୗ࡟ , ᭩㠃࡟ࡼࡿᝈ⪅࠿ࡽࡢྠពࢆ

ᚓࡓୖ࡛⾜ࡗࡓ . ᑐ㇟ࡣእ᮶࡟࡚ᣢ⥆ᛶᚰᡣ⣽ືࡢὝㄪᚊ⥔ᣢࢆ┠ⓗ࡟ , ࣋ࣉࣜࢪࣝሷ㓟 ሷỈ࿴≀㘄 (100 㹼 200 mg/day) ࢆ⤒ཱྀᢞ୚ࡋ࡚࠸ࡿᝈ⪅ 5 ྡ࡜ࡋࡓ . ᥇⾑᪥ࡢᮅࡣᑐ㇟

ᝈ⪅࡟࣋ࣉࣜࢪࣝሷ㓟ሷỈ࿴≀㘄ࡢ᭹⏝ࢆ୰Ṇࡉࡏ , ᮶㝔᫬࡟᥇⾑ࡋࡓ .

12

2 㸧  ᐃ᪉ἲ

➨ 1 㡯 2), 3), 4) ࡟♧ࡋࡓ᪉ἲ࡟࡚ヨᩱࢆㄪ〇ࡋ , ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࢆ ᐃࡋࡓ .

3 㸧 ⤫ィฎ⌮

⤖ᯝࡣ඲࡚ᖹᆒ್sᶆ‽೫ᕪ (mean s S.D.) ࡛♧ࡋࡓ . ࡲࡓ , ⢭ᗘࡣኚືಀᩘ࡜ࡋ࡚♧ࡋ ,

┿ᗘࡣ⌮ㄽ್࠿ࡽࡢ஋㞳ᗘ࡛♧ࡋࡓ .

➨ 3 ⠇ ⤖ᯝ

➨ 1 㡯 ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲࡢᵓ⠏

1 㸧 HPLC ᮲௳ࡢ᭱㐺໬

Taguchi ࡽ

ࡢ᪉ἲ࡟‽ᣐࡋ࡚ , HPLC ࡢ⛣ື┦ࢆ 2% (w/v) ࢺ࢚ࣜࢳࣝ࢔࣑ࣥྵ᭷ 10 mM ࣜࣥ㓟஧Ỉ⣲࣒࢝ࣜ࢘⦆⾪ᾮ : ࢔ࢭࢺࢽࢺࣜࣝ (60: 40, v/v) , ࣒࢝ࣛ࡜ࡋ࡚ C

࣒࢝ࣛ

(4.6 ™ 150 mm, 4.5 Pm particle size) ࢆ⏝࠸࡚࣋ࣉࣜࢪࣝࡢ ᐃࢆヨࡳࡓ . ࡋ࠿ࡋ࡞ࡀࡽ࣋ࣉ

ࣜࢪࣝࡢ⁐ฟ࡟ 30 ศ௨ୖせࡋࡓࡓࡵ , C

࣒࢝ࣛ࡟ኚ᭦ࡋ , ࡲࡓ , ⾑₢⏤᮶ࡢࣆ࣮ࢡࢆ࣋

ࣉࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝ⏤᮶ࡢࣆ࣮ࢡ࡜ศ㞳ࡍࡿࡓࡵ࡟ , ⛣ື┦ࡢ࢔ࢭࢺࢽࢺࣜࣝ࠾

ࡼࡧ࣓ࢱࣀ࣮ࣝࡢ๭ྜࢆㄪᩚࡋࡓ .

2 㸧 ≉␗ᛶ

ࣈࣛࣥࢡ⾑₢࠾ࡼࡧ 250 ng/mL ࣋ࣉࣜࢪࣝ࡜ 2.5 g/mL 1- ࢼࣇࢺ࣮ࣝ ࡜࡞ࡿࡼ࠺࡟ࡑ

ࢀࡒࢀࢆῧຍࡋࡓ⾑₢ࡼࡾᚓࡓヨᩱࡢࢡ࣐ࣟࢺࢢ࣒ࣛࢆ Fig. 3 ࡟♧ࡋࡓ . ࣈࣛࣥࢡ⾑₢࠿

ࡽࡣ࣋ࣉࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝ࡟ᖸ΅ࡍࡿࣆ࣮ࢡࡣ᳨ฟࡉࢀ࡞࠿ࡗࡓ (Fig. 3A). ࣋ࣉ

ࣜࢪࣝ࠾ࡼࡧ 1- ࢼࣇࢺ࣮ࣝ⏤᮶ࣆ࣮ࢡࡢ⁐ฟ᫬㛫ࡣࡑࢀࡒࢀ 12.6 ศ࠾ࡼࡧ 7.5 ศ࡛࠶

ࡾ (Fig. 3B), ⾑₢⏤᮶ࡢ 5.3, 6.7, 10 ศ௜㏆ࡢࣆ࣮ࢡ࡜ࡣ᏶඲࡟ศ㞳ࡍࡿࡇ࡜ࡀ࡛ࡁࡓ .

ࡲࡓ , IS ೃ⿵࡜ࡋ࡚ 1- ࣄࢻࣟ࢟ࢩ -2- ࢼࣇࢺ࢚㓟 , p- ࢔࣑ࣀᏳᜥ㤶㓟࢚ࢳࣝࡸ p- ࢔࣑ࣀᏳᜥ

13

㤶㓟ࣈࢳࣝࢆヨ⾜ࡋࡓࡶࡢࡢ , 1- ࣄࢻࣟ࢟ࢩ -2- ࢼࣇࢺ࢚㓟ࡣ⁐ฟ᫬㛫ࡀ࣋ࣉࣜࢪࣝ࡟㏆ࡃ , p- ࢔࣑ࣀᏳᜥ㤶㓟࢚ࢳࣝ , p- ࢔࣑ࣀᏳᜥ㤶㓟ࣈࢳࣝࡢࣆ࣮ࢡࡣ⾑₢⏤᮶ࣆ࣮ࢡ࡟ᖸ΅ࡉࢀ

ࡓࡓࡵ , IS ࡜ࡋ࡚㐺ࡉ࡞࠿ࡗࡓ . ࡉࡽ࡟ , ࣋ࣉࣜࢪࣝ࡜ࡢే⏝㢖ᗘࡢ㧗࠸ 32 ✀㢮ࡢ་⸆ရ

ࢆ⛣ື┦࡟⁐ゎࡋࡓࡶࡢࢆヨᩱ࡜ࡋ࡚ ᐃࡋࡓ࡜ࡇࢁ , 5 ✀㢮ࡢ་⸆ရ㸦ࣂࣝࢧࣝࢱࣥ , ࣟ ࢧࣝࢱࣥ , ࣡ࣝࣇ࢓ࣜࣥ , ࢢࣜࢡࣛࢪࢻ , ࣟࣂࢫࢱࢳࣥ㸧࡛࣋ࣉࣜࢪࣝ࠶ࡿ࠸ࡣ IS ⏤᮶ࣆ

࣮ࢡࡢ㏆ഐ࡟ࣆ࣮ࢡࡀᚓࡽࢀࡓࡀ , ࣈࣛࣥࢡ⾑₢࡟ࡇࢀࡽࡢ་⸆ရࢆῧຍࡋࡓᚋ , ᢳฟࡋ

࡚ᚓࡽࢀࡓ࡝ࡢヨᩱࡶ࣋ࣉࣜࢪࣝ࠾ࡼࡧ IS ⏤᮶ࡢࣆ࣮ࢡࢆᖸ΅ࡋ࡞࠿ࡗࡓ (Table 2).

Fig. 3. Typical Chromatograms of Blank Plasma (A) and Plasma Spiked with 250 ng/mL of Bepridil and 2.5 Pg/mL IS (1-naphthol) (B)

Peaks a and b originate from plasma. The retention times of bepridil and IS are 12.6 and 7.5 min, respectively.

IS bepridil12.6

7.5ba4.0

0.0 12.08.0 16.0

ba4.0

0.0 12.08.0 16.0

A B

Absorbance, 254 nm

Retention time (min)

14

Table 2. Retention Time and Effect of Extraction of Cardiovascular Medicines Frequently Co-administered to Patients with Bepridil

Chemical name Brand name*

Amlodipine besilate Amlodin^䒆 3.9

Cilnidipine Atelec^䒆 No peak

Olmesartan medoxomil Olmetec^䒆 10.3

Valsartan Diovan^䒆 13.4

Nilvadipin Nivadil^䒆 No peak

Nicorandil Sigmart^䒆 2.6

Verapamil hydrochloride Vasolan^䒆 4.2

Warfarin potassium Warfarin^䒆 13.9

Trichlormethiazide Fluitran^䒆 3.9

Candesartan cilexetil Blopress^䒆 No peak

Aspirin Bufferin^䒆 3.5

Fursultiamine hydrochloride Alinamin F^䒆 2.0

Doxazosin mesilate Cardenalin^䒆 No peak

Ticlopidine hydrochloride Panaldine^䒆 10.8

Isosorbide mononitrate (MSDN) Itorol^䒆 No peak

Losartan potassium Nu-Lotan^䒆 8.0

Clopidogrel sulfate Plavix^䒆 No peak

Diltiazem hydrochloride Herbesser^䒆 3.0

Furosemide Lasix^䒆 4.6

Metildigoxin (methyldigoxin) Lanirapid^䒆 6.9

Amezinium metilsulfate Risumic^䒆 10.0

Propranolol hydrochloride Inderal^䒆 2.5

Glimepiride Amaryl^䒆 No peak

Gliclazide Glimicron^䒆 13.6

Metformin hydrochloride Glycoran^䒆 1.4

Rosuvastatin calcium Crestor^䒆 8.4

Allopurinol Zyloric^䒆 1.6

Pitavastatin calcium Livalo^䒆 10.7

Bisoprolol fumarate Maintate^䒆 No peak

Digoxin Digosin^䒆 No peak

Enalapril maleate Renivace^䒆 No peak

Pranlukast hydrate Onon^䒆 No peak

Retention time (min) Before extraction After extraction

Calcium channel blocker

ARB

Anti-platelet agents

Antidiabetic agents

Others Diuretics

Inotropic agents b-blocker

Anti-anginal agents

No peak - - -

No peak No peak

-

- -

No peak -

- -

- -

- -

- -

- -

- -

- - - - - - -

Bepridil hydrichloride hydrate Bepricor^䒆 12.6

1-Naphtol (IS) - 7.5

12.6 7.5

*: The brand names approved in Japan.

-

No peak

15

3 㸧 ┤⥺ᛶ

⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ 5 Ⅼ (25 㹼 1,000 ng/mL) ࡢࣆ࣮ࢡ㠃✚ẚ ( ࣋ࣉࣜࢪࣝ /IS) ࡣ⃰

ᗘ࡟౫ᏑࡋࡓⰋዲ࡞┤⥺ᛶࢆ♧ࡋࡓ (Table 3, Fig. 4). ࡑࢀࡒࢀࡢ⃰ᗘ࡟࠾ࡅࡿ ᐃ⢭ᗘࡣ 0.5 㹼 4.6%,  ᐃ┿ᗘࡣ 97.7 㹼 103.0% ࡛࠶ࡾ (Table 3), ┦㛵ಀᩘࡣ 0.999 ௨ୖ࡜࡞ࡗࡓ (Fig. 4).

Table 3. Linearity of the Relationship between Nominal and Measured Concentrations of Bepridil (n = 6)

Fig. 4. Calibration Curve of Bepridil

Nominal concentration (ng/mL)

Measured concentration (ng/mL, mean ·S.D.)

Accuracy (%) Precision

(CV%) 25

100 250 500 1000

25.8 ·1.1 99.4 ·4.6 244.2 ·2.8 499.6 ·2.6 998.5 ·7.0

4.4 4.6 1.2 0.5 0.7

103.0 99.4 97.7 99.9 99.8

y = 0.0071x + 0.0655 r = 0.999

0.0 2.0 4.0 6.0 8.0

0 200 400 600 800 1000

Peak area ratio (bepridil/IS)

Bepridil concentration (ng/mL)

16

4 㸧  ᐃឤᗘ

௒ᅇᵓ⠏ࡋࡓ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ࡟࠾ࡅࡿ ᐃ㝈⏺࠾ࡼࡧᐃ㔞㝈⏺ࡣࡑࢀࡒࢀ

5, 10 ng/mL ࡛࠶ࡾ , S/N (signal/noise) ẚࡣࡑࢀࡒࢀ 3.0 ࠾ࡼࡧ 8.0 ௨ୗ࡛࠶ࡗࡓ ( ࢹ࣮ࢱ ᮍグ㍕ ). ࡲࡓ , ᐃ㔞㝈⏺࡟࠾ࡅࡿ ᐃ⢭ᗘ࠾ࡼࡧ ᐃ┿ᗘࡣࡑࢀࡒࢀ 3.2% ࠾ࡼࡧ 95.1%

࡛࠶ࡗࡓ (Table 4).

Table 4. Validation of Bepridil Determination at Lower Concentration

5 㸧 ᪥ෆ࠾ࡼࡧ᪥ᕪ෌⌧ᛶ

3 Ⅼࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ (25, 250, 1,000 ng/mL) ࡟࠾࠸࡚ ,  ᐃ⢭ᗘࡣ᪥ෆ࠾ࡼࡧ᪥

㛫࡛ 5.0% ௨ୗࡔࡗࡓ . ᪥ෆ࡟࠾ࡅࡿ ᐃ┿ᗘࡣ 98.0 㹼 101.6% ࡛࠶ࡾ , ᪥㛫࡛ࡣ 96.1 㹼

100.8% (Table 5) ࡛࠶ࡗࡓ . ࡲࡓ , ᢳฟᅇᩘ࡟౫Ꮡࡋ࡚ ᐃ⢭ᗘ࡜ ᐃ┿ᗘࡣྥୖࡋࡓ ( ࢹ

࣮ࢱᮍグ㍕ ).

Table 5. Validation of Quality Control Samples Obtained during Within-day and Between-day Validation

Nominal concentration (ng/mL)

Measured concentration (ng/mL)

Precision (CV%)

Accuracy (%)

5 䠉 䠉 䠉

10 9.5㼼0.3 3.2 95.1

Measured concentration represents the mean㼼S.D. of 4 determinations.

Quolity control sample Low Medium High

Nominal concentration

(ng/mL) 25 250 1000

Within-day (n = 9) Mean ·S.D. (ng/mL) Precision (CV%)

24.7 ·1.2 253.9 ·11.6 979.7 ·49.4

5.0 4.6 5.0

Between-day (n = 4) Mean rS.D. (ng/mL) Precision (CV%)

Accuracy (%) 98.9 101.6 98.0

Accuracy (%)

25.2 ·0.8 250.8 ·2.8 961.5 ·38.2

3.1 1.1 4.0

100.8 100.3 96.1

17

6 㸧 ᢳฟຠ⋡

3 Ⅼࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ (25, 250, 1,000 ng/mL) ࡟࠾ࡅࡿᢳฟຠ⋡ࡣ 104.4r3.5%, 109.9±1.1%, 110.8r1.0% ࡛࠶ࡗࡓ ( ࢹ࣮ࢱᮍグ㍕ ). IS ࡢᢳฟຠ⋡ࡣ 22.9 㹼 24.8% ࡛࠶ࡗ ࡓ .

7 㸧 ෾⤖⾑₢୰ࡢಖᏑᛶ

㸫 20 Υୗ࡟࠾ࡅࡿ 25, 250, 1,000 ng/mL ࡢ࣋ࣉࣜࢪࣝࡢ⃰ᗘࡣ 21 ᪥ࡲ࡛෾⤖ಖᏑ๓࡟

࠾ࡅࡿ⃰ᗘࡢ 100% ࢆಖᣢࡋ࡚࠾ࡾ , Ⰻዲ࡛࠶ࡗࡓ (Fig. 5) ࡀ , ಖᏑᮇ㛫ࡢᘏ㛗࡟క࠸⾑

₢⏤᮶ࣆ࣮ࢡࡀዃ㞧ࣆ࣮ࢡ࡜ࡋ࡚ฟ⌧ࡋࡓ . ࡲࡓ , 250, 1,000 ng/mL ࡛ࡣ 42 ᪥ࡲ࡛෾⤖ಖ Ꮡ๓ࡢ࣋ࣉࣜࢪࣝ⃰ᗘࢆ⥔ᣢࡋ࡚࠸ࡓࡶࡢࡢ , 25 ng/mL ࡛ࡣ 42 ᪥ࡲ࡛࡟ 82.6% ࡟ῶᑡࡋ ࡓ .

Fig. 5. Time-course of Stability of Bepridil Stored in Plasma at 㸫 20 Υ

Quality control samples of law (), medium () and high (ᇞ) concentration were prepared to 25, 250, 1,000 ng/mL, respectively. Each data represents the meansS.D. of 3 samples.

8 㸧 ᝈ⪅᳨యࡢ ᐃ

ᚰᡣ⣽ືࢆ᭷ࡍࡿᝈ⪅ 5 ྡࡢ⾑₢୰ࡢ࣋ࣉࣜࢪࣝ⃰ᗘࢆ ᐃࡋࡓ . ᥇⾑ࡣࡑࢀࡒࢀࡢ ᝈ⪅ࡀ࣋ࣉࣜࢪࣝሷ㓟ሷỈ࿴≀㘄ࢆ᭹⏝ࡍࡿ┤๓࡟⾜ࡗࡓ . ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡢᢞ୚

0%

20%

40%

60%

80%

100%

120%

0 7 14 21 28 35 42

Time (day)

Stability ^Low

Medium High

18

┤๓್ࡣ 233.9 㹼 347.4 ng/mL ࡛࠶ࡾ , 5 ྡࡢᚰ㟁ᅗ࡟࠾ࡅࡿἼᙧࡣ SR ࢆ♧ࡋ࡚࠸ࡓ

(Table 6).

Table 6. Background and Concentration of Bepridil in Plasma of 5 Patients with Af

➨ 4 ⠇ ⪃ᐹ

Ng ࡽ

࠾ࡼࡧ Taguchi ࡽ

ࡀሗ࿌ࡋࡓ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ࡛ࡣ C

࢝ࣛ

࣒ࢆ౑⏝ࡋ , ⁐㞳ᾮ࡟ࡣ࣓ࢱࣀ࣮ࣝࢆ⏝࠸࡚࠸ࡓ . ࡑࡇ࡛ࡲࡎ , ᮏ◊✲࡟࠾࠸࡚ࡶྠᵝࡢ ᮲௳࡟ࡼࡾᐃ㔞ࢆヨࡳࡓࡀ , ࣋ࣉࣜࢪࣝࡢ⁐ฟࡀ㐜ࡃ , ㎿㏿࡞ ᐃ࡟ࡣ㐺ࡉ࡞࠿ࡗࡓ . ࡑ ࡇ࡛ , C

࣒࢝ࣛࢆ⏝࠸᳨࡚ウࡋࡓࡀ , ࣋ࣉࣜࢪࣝࡣ᳨ฟࡉࢀࡓࡶࡢࡢ⾑₢୰ᡂศ࡟ࡼࡾᖸ

΅ࡉࢀࡓࡓࡵ , ࡉࡽ࡟⁐㞳ᾮࢆኚ᭦ࡋ , ⾑₢⏤᮶ᡂศ࡜࣋ࣉࣜࢪࣝࢆศ㞳ࡍࡿࡇ࡜ࡀ࡛ࡁ

ࡓ . IS ࡟ࡣ 1- ࢼࣇࢺ࣮ࣝࢆ⏝࠸ࡿࡇ࡜࡛࣋ࣉࣜࢪࣝ⏤᮶ࡢࣆ࣮ࢡ࡜ࡢศ㞳ࡣⰋዲ࡜࡞ࡾ

(Fig. 3), ᮏἲࢆ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ࡜ࡋ࡚☜❧ࡍࡿࡇ࡜ࡀ࡛ࡁࡓ . ࡲࡓ , Ng ࡽ

ࡣ n- ࣊࢟ࢧࣥ࡟ࡼࡿ 1 ᅇᢳฟἲ࡟ࡼࡗ࡚⾑₢࠿ࡽ࣋ࣉࣜࢪࣝࢆᢳฟࡋࡓሙྜ , ᢳฟຠ⋡

ࡣ 51.6% ࡛࠶ࡗࡓࡇ࡜ࢆሗ࿌ࡋ࡚࠸ࡿ . ࡇࢀ࡜ྠᵝࡢ᪉ἲࢆ࡜ࡗࡓ࡜ࡇࢁ , IS ࡢᢳฟࡣ

୙༑ศ࡛࠶ࡾ , ᢳฟຠ⋡ࡶ୙Ᏻᐃ࡛࠶ࡗࡓ . ࡑࡇ࡛ , n- ࣊࢟ࢧࣥ࡟ࡼࡿᢳฟ᧯సࢆ 2 ᅇ࡜

ࡍࡿࡇ࡜࡛ 1- ࢼࣇࢺ࣮ࣝࡢᢳฟຠ⋡ࢆᨵၿࡋ , ᐃ㔞ࢆྍ⬟࡜ࡋࡓ . ᢳฟ᮲௳ࡣሷᇶᛶ⸆≀

࡛࠶ࡿ࣋ࣉࣜࢪࣝࡢᢳฟຠ⋡ࢆୖࡆࡿࡓࡵ࡟ᢳฟ㐣⛬࡟࠾ࡅࡿ pH ࡣ 7.4 ࡟ㄪᩚࡋࡓࡓࡵ ,

Patient no. Age (years)

Precision (CV%) 85

61 69 65 84

312.7 ·2.0 309.3 ·1.8 327.7 ·15.9 300.4 ·4.9 233.5 ·3.7

0.6 0.6 4.9 1.6 1.6 Gender

(M/F)

Dose (mg/day)

Measured concentration (ng/mL, mean ·S.D.) F

M F F F

100 200 100 200 100 1

2 3 4 5

Weight (kg) 51.0 52.9 57.0 46.2 68.4

19

ᙅ㓟ᛶ໬ྜ≀࡛࠶ࡿ 1- ࢼࣇࢺ࣮ࣝࡢᢳฟຠ⋡ࡣపୗࡋࡓ . ࡋ࠿ࡋ , ௚ࡢ IS ೃ⿵⸆≀࡛࠶

ࡿ 1- ࣄࢻࣟ࢟ࢩ -2- ࢼࣇࢺ࢚㓟 , p- ࢔࣑ࣀᏳᜥ㤶㓟࢚ࢳࣝ , p- ࢔࣑ࣀᏳᜥ㤶㓟ࣈࢳࣝࡼࡾࡶ

㧗࠸ᢳฟຠ⋡࡛࠶ࡗࡓࡇ࡜࡜࢔ࣝ࢝ࣜ᮲௳ୗ࠶ࡿ࠸ࡣ㓟ᛶ᮲௳ୗ࡞࡝ pH ࢆኚ࠼᳨࡚ウ ࡋࡓ࡜ࡇࢁ , ᢳฟຠ⋡ࡀ᭱ࡶᏳᐃࡋ࡚࠸ࡓࡇ࡜࠿ࡽ 1- ࢼࣇࢺ࣮ࣝࢆ IS ࡜ࡋ࡚᥇⏝ࡋࡓ .

ᮏ ᐃἲ࡟࠾ࡅࡿ࣋ࣉࣜࢪࣝࡢ᳨㔞⥺ࡣ , 25 㹼 1,000 ng/mL ࡢ⃰ᗘ⠊ᅖ࡟࠾࠸࡚࡯ࡰཎⅬ

ࢆ㏻ࡿⰋዲ࡞┤⥺ᛶࢆ♧ࡋࡓ (Table 3, Fig. 4). ࡉࡽ࡟ , 25, 250, 1,000 ng/mL ࡟ㄪ〇ࡋࡓ࣋

ࣉࣜࢪࣝῧຍ⾑₢࡟࠾ࡅࡿ᪥ෆ࠾ࡼࡧ᪥ᕪ෌⌧ᛶࡣ , ኚືಀᩘ࡞ࡽࡧ⌮ㄽ್࠿ࡽࡢ஋㞳ᗘ ࡀඹ࡟ 5% ௨ෆ࡛࠶ࡾ , ⢭ᗘ࡜┿ᗘࡣⰋዲ࡛࠶ࡗࡓ (Table 5). Ng ࡽࡢ᪉ἲ

࡛ࡣ⢭ᗘ࠾

ࡼࡧ┿ᗘࡣࡑࢀࡒࢀ 2.0 㹼 6.3%, 98.2 㹼 102.6% ࡜ሗ࿌ࡉࢀ࡚࠾ࡾ , ᡃࠎࡢ᪉ἲࡣࡇࢀࡽ࡜

࡯ࡰྠ➼࡛࠶ࡗࡓ . ࡇࢀࡼࡾ , ᮏ ᐃἲࡣ 25 㹼 1,000 ng/mL ࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰

ᗘࡢṇ☜࡞ ᐃࡀྍ⬟࡛࠶ࡿࡇ࡜ࡀ♧ࡉࢀࡓ . ࡲࡓ , ᮏ ᐃἲ࡛ࡣ 5 ng/mL ᳨࡛ฟ㝈⏺௨

ୗ࡜࡞ࡾ , 10 ng/mL ࡛ࡣ⢭ᗘ࠾ࡼࡧ┿ᗘࡶⰋዲ࡛࠶ࡗࡓࡇ࡜࠿ࡽ , 10 ng/mL ࢆᮏ ᐃἲࡢ

ᐃ㔞㝈⏺࡜ࡋࡓ (Table 4). Ng ࡽ

ࡣ IS ࡜ࡋ࡚〇⸆௻ᴗ࠿ࡽࡢ⸆ရᥦ౪ࡀᚲせ࡞࣋ࣉࣜ

ࢪࣝㄏᑟయ (Org30270) ࢆ⏝࠸ , ࣄࢺ⾑₢ 500 PL ࢆ⏝࠸ࡓሙྜࡢᐃ㔞㝈⏺ࡀ 10 ng/mL ࡔ ࡗࡓࡇ࡜ࢆሗ࿌ࡋ࡚࠸ࡿ . ࡲࡓ , Taguchi ࡽ

ࡣ IS ࢆ⏝࠸ࡎ࡟⤯ᑐ᳨㔞⥺ἲࢆ⏝࠸࡚࠸

ࡿ . ᮏ ᐃἲࡣ IS ࡜ࡋ࡚ධᡭࡀᐜ᫆࠿ࡘศ㞳ࡀⰋዲ࡞ 1- ࢼࣇࢺ࣮ࣝࢆ⏝࠸࡚ , ᪤ሗ࡜ྠ

➼ࡢឤᗘ࡛⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡢ ᐃࡀྍ⬟࡛࠶ࡿࡇ࡜ࡀ♧ࡉࢀࡓ .

ᝈ⪅᳨యࡣ་⒪ᶵ㛵࡛᥇⾑ᚋ࡟⾑₢ࢆศ㞳ࡋ , ෾⤖ಖᏑࡢᚋ࡟ᦙ㏦ࡋ࡚ ᐃࢆ⾜࠺ࡓࡵ ,

෾⤖ಖᏑ᫬ࡢ⾑₢୰࣋ࣉࣜࢪࣝࡢᏳᐃᛶࢆ᳨ウࡍࡿᚲせࡀ࠶ࡿ . ࡑࡇ࡛ , ᝈ⪅ࡢ⾑₢୰࣋

ࣉࣜࢪࣝ⃰ᗘࢆ᝿ᐃࡋࡓୖ࡛⾑₢ࡢ෾⤖࡟ࡼࡿᙳ㡪ࢆ☜ㄆࡍࡿ┠ⓗ࡜ࡋ , 25, 250, 1,000

ng/mL ࡢ 3 ⃰ᗘ࡟ㄪ〇ࡋࡓ࣋ࣉࣜࢪࣝῧຍ⾑₢ࢆ෾⤖ಖᏑࡋ࡚ , ࣋ࣉࣜࢪࣝࡢᏳᐃᛶࢆ

⤒᫬ⓗ࡟᳨ウࡋࡓ . ࡑࡢ⤖ᯝ , ᙜ᪥࡟ㄪ〇ࡋࡓヨᩱ࡜෾⤖ಖᏑࡋࡓヨᩱ࡟࠾ࡅࡿ࣋ࣉࣜࢪ

ࣝ⃰ᗘࡣ , ྛ⃰ᗘ࡟࠾࠸࡚ 21 ᪥┠ࡲ࡛ࡣ࠸ࡎࢀࡶᕪࡀ࡞࠸ࡇ࡜ࡀ♧ࡉࢀࡓ . ࡋ࠿ࡋ࡞ࡀ

ࡽ , 42 ᪥┠ࡲ࡛࡟ప⃰ᗘ࡛ࡢ࣋ࣉࣜࢪࣝࡢ⃰ᗘపୗࡀㄆࡵࡽࢀࡓࡇ࡜࠿ࡽ (Fig. 5), ᥇⾑

࠿ࡽ ᐃࡲ࡛ 3 㐌㛫ࡣಖᏑྍ⬟࡛࠶ࡿࡇ࡜ࡀ♧ࡉࢀࡓ .

⮫ᗋ࡟࠾࠸࡚ , 1 ྡࡢᝈ⪅࡟」ᩘࡢ⸆๣ࡀ⏝࠸ࡽࢀࡿࡇ࡜ࡣࡲࢀ࡛ࡣ࡞ࡃ , ≉࡟ᚠ⎔ჾ

20

㡿ᇦࡢ⑌ᝈ࡟࠾࠸࡚ࡣከ✀㢮ࡢ⸆≀ࡀే⏝ࡉࢀࡿሙྜࡀከ࠸ . ࡲࡓ , ే⏝⸆≀ࡢ࡯࡜ࢇ࡝

ࡣ㛗ᮇ㛫ᢞ୚ࡉࢀࡿࡓࡵ , 㧗㢖ᗘ࡟⏝࠸ࡽࢀࡿ⸆≀࡟ࡘ࠸࡚ࡣ , ࠶ࡽ࠿ࡌࡵ࣋ࣉࣜࢪࣝࡢ  ᐃ࡟ᑐࡍࡿᖸ΅ࡢ᭷↓ࢆ᳨ウࡍࡿᚲせࡀ࠶ࡿ . ࡑࡇ࡛ , ࣋ࣉࣜࢪࣝ࡟ࡼࡿ἞⒪ࢆཷࡅ࡚

࠸ࡿᝈ⪅ࡀ౑⏝ࡋ , ࠿ࡘే⏝㢖ᗘࡢ㧗࠸ 32 ✀㢮ࡢ⸆≀࡟ࡘ࠸࡚ᐃ㔞ጉᐖࡢ᭷↓ࢆ᳨ウࡋ ࡓ . ࡑࡢ⤖ᯝ , ࡑࢀࡒࢀࢆ⛣ື┦࡟⁐ゎࡋࡓヨᩱࢆ┤᥋ ᐃࡋࡓሙྜ࡛ࡣ , 5 ✀㢮ࡢ⸆≀࡛

࣋ࣉࣜࢪࣝ࠾ࡼࡧ IS ࡢ⁐ฟ᫬㛫㏆ഐ࡟ࣆ࣮ࢡࡀฟ⌧ࡋࡓ (Table 2). ࡋ࠿ࡋ , ࡇࢀࡽࡢ⸆

≀࡟ᑐࡋ࡚⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃ᫬࡜ྠᵝ࡟ n- ࣊࢟ࢧࣥ࡟ࡼࡿᢳฟ᧯సࢆຍ࠼ࡓሙྜ

࡟ࡣ , ࠸ࡎࢀࡢ⸆≀ࡶࣆ࣮ࢡࡣᾘኻࡋࡓ . ࡋࡓࡀࡗ࡚ , ᮏ ᐃἲ࡟࠾࠸࡚௒ᅇ᳨ウࡋࡓ⸆

≀ࡢᮍኚ໬య࡟ࡼࡾ࣋ࣉࣜࢪࣝࡢ ᐃࡀጉᐖࡉࢀࡿྍ⬟ᛶࡣప࠸ࡇ࡜ࡀ♧ࡉࢀࡓ . ௨ୖࡢ

⤖ᯝ࠿ࡽ , ᮏ ᐃἲ࡟ࡼࡾᝈ⪅ࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ ᐃྍ⬟࡛࠶ࡿ࡜⪃࠼ࡽࢀࡓ .

ࡲࡓ , ⮫ᗋ࡛ Af ࡟ᑐࡋ࡚࣋ࣉࣜࢪࣝ (100 㹼 200 mg/day) ࢆ᭹⏝ࡋ࡚࠸ࡿᝈ⪅ࡢᢞ୚┤

๓࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࢆ ᐃࡋࡓ࡜ࡇࢁ , ࡑࡢ್ࡣ 233.9 㹼 347.4 ng/mL ࡛࠶ࡗ ࡓ (Table 6). Benet ࡽ

ࡣ࣋ࣉࣜࢪࣝࢆ 200 mg/day (1 ᪥ 2 ᅇ ) ᭹⏝ࡋ࡚࠸ࡿ 28 ྡࡢᝈ⪅

ࡢᢞ୚┤๓࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ 456 s 326 ng/mL ࡛࠶ࡗࡓࡇ࡜ࢆሗ࿌ࡋ࡚࠸

ࡿ . ࡲࡓ , Taguchi

ࡽࡣ , ୙ᩚ⬦ࡢ἞⒪࡜ࡋ࡚ 100 㹼 200 mg/day ࡢ࣋ࣉࣜࢪࣝࢆ᭹⏝ࡋ࡚

࠸ࡿ 34 ྡࡢ᪥ᮏேᝈ⪅࡟࠾ࡅࡿᢞ୚ᚋ 2 㹼 24 ᫬㛫್ࡣ 100 㹼 1,500 ng/mL ࡛࠶ࡗࡓࡇ࡜

ࢆሗ࿌ࡋ࡚࠸ࡿ . ࡑࢀࡒࢀࡢ◊✲ࡣ , ᥇⾑᫬㛫ࡀ⿕㦂⪅࡟ࡼࡗ࡚␗࡞ࡾ , ೺ᖖᡂே

࠶ࡿ

࠸ࡣᮎᮇ⭈୙඲ (End stage renal disease: ESRD),

ࡶࡋࡃࡣᚰ⑌ᝈࢆᣢࡓ࡞࠸ᝈ⪅࡟࠾ࡅ

ࡿ༢ᅇᢞ୚᫬ࡢ⾑୰⸆≀⃰ᗘ᥎⛣࡛࠶ࡿ࡞࡝ , ᚲࡎࡋࡶྠࡌ᪉ἲࢆ࡜ࡗ࡚࠾ࡽࡎ ,

ྠ ࡌ᥇⾑Ⅼ࡛ホ౯ࡋࡓᮏ◊✲࡛ᚓࡽࢀࡓ್࡜ࡣ┤᥋ẚ㍑ࡍࡿࡇ࡜ࡣ࡛ࡁ࡞࠸ . ࡋ࠿ࡋ࡞ࡀࡽ ,

௒ᅇᚓࡽࢀࡓ⤖ᯝࡣࡇࢀࡲ࡛ࡢሗ࿌࡜ࡢ㛫࡟኱ࡁ࡞ᕪࡢ࡞࠸ࡶࡢ࡛࠶ࡗࡓ .

ᮏ◊✲࡛ࡣࣄࢺ⾑₢୰࡟࠾ࡅࡿ࣋ࣉࣜࢪࣝ⃰ᗘࡢ⡆౽࡞ ᐃἲࢆ☜❧ࡋ , ే⏝⸆࡜ࡋ࡚

⏝࠸ࡽࢀࡿ⸆≀࡟ࡼࡿᐃ㔞࡬ࡢᖸ΅ࡀ࡞࠸ࡇ࡜ࢆ☜ㄆࡋࡓ . ࡇࡢ᪉ἲࢆ⏝࠸࡚ḟࡢ❶࡛ࡣ ,

⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ࡜⮫ᗋຠᯝࢆホ౯ࡍࡿ࡟࠶ࡓࡗ࡚ࡢ㐺ษ࡞᥇⾑᫬㛫ࢆỴᐃࡍࡿࡓࡵ

ࡢ᳨ウࢆ⾜ࡗࡓ .

21

➨ 2 ❶ ⤒ཱྀᢞ୚ᚋ࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡢࣔࢽࢱࣜࣥࢢ࣏࢖ࣥࢺ ࡢጇᙜᛶ࡟㛵ࡍࡿ᳨ウ

➨ 1 ⠇ ⥴ゝ

ᢠ୙ᩚ⬦⸆࡛࠶ࡿ࣋ࣉࣜࢪࣝࡣ , Af ࡟ᑐࡋ࡚⏝㔞౫Ꮡⓗ࡟㝖⣽ືຠᯝࢆ♧ࡍࡀ , ๪స⏝

࡜ࡋ࡚ QT 㛫㝸ᘏ㛗ࢆక࠺㔜⠜࡞ദ୙ᩚ⬦స⏝ࢆ⏕ࡌࡿྍ⬟ᛶࡶᣦ᦬ࡉࢀ࡚࠸ࡿ .

ࡑࡢ ࡓࡵ , ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ࡜㝖⣽ືຠᯝ࠾ࡼࡧ๪స⏝Ⓨ⌧࡜ࡢ㛫࡟ࡣ┦㛵ᛶࡀ࠶ࡿ࡜⪃

࠼ࡽࢀ࡚࠸ࡿ . ࡋ࠿ࡋ , ᚰ➽⣽⬊ෆ࡬ࡢ࣋ࣉࣜࢪࣝࡢྲྀࡾ㎸ࡳ࠾ࡼࡧ⵳✚ࡀ⏕ࡌࡿ࡜࠸࠺

ሗ࿌ࡣ࠶ࡿࡶࡢࡢ ,

⸆⌮స⏝Ⅼ࡟࠾ࡅࡿ⤌⧊ෆ⃰ᗘ࡜⾑₢୰⃰ᗘࡢ㛵ಀ࠶ࡿ࠸ࡣ , ࡇ

ࢀࡽࡢ⃰ᗘ࡜⮫ᗋຠᯝࡢ㛵ಀ࡟ࡘ࠸࡚ヲ⣽࡞᳨ウࡣ⾜ࢃࢀ࡚࠾ࡽࡎ , 㐺ษ࡞⾑୰⸆≀⃰ᗘ ᇦࡣ༑ศ࡟᫂ࡽ࠿࡟ࡉࢀ࡚࠸࡞࠸ .

୍⯡ⓗ࡟ , ⸆≀ᢞ୚ᚋࡢ⾑₢୰⃰ᗘࡣᢞ୚ᚋࡢ⤒㐣᫬㛫࡟ࡼࡾኚ໬ࡍࡿࡇ࡜࠿ࡽ , TDM

ࢆᐇ᪋ࡍࡿ㝿࡟ࡣ , ⾑₢୰⃰ᗘࢆホ౯ࡍࡿࡓࡵ࡟࡝ࡢ᫬Ⅼ࡛᥇⾑ࡍࡿ࠿ , ࡍ࡞ࢃࡕᢞ୚ᚋ

࠿ࡽḟᅇᢞ୚ࡲ࡛ࡢ㛫ࡢ࡝ࡢ᫬Ⅼ࡛᥇⾑ࡍࡿ࠿ , ࠾ࡼࡧᢞ୚㛤ጞ࠿ࡽఱ᪥┠࡟᥇⾑ࢆࡍࡿ

࠿ , ࡞࡝ࢆᐃࡵࡿࡇ࡜ࡀ㔜せ࡛࠶ࡿ . ᖺ㱋 , ᛶู , ⏕ά⩦័ࡸ⑓ែ࡞࡝ࡢከᵝᛶࡶ࠶ࡾ , ࣄ ࢺࡢ⸆≀ືែࡣಶయᕪࡀ኱ࡁࡃ , ᭱㧗⾑୰⃰ᗘ (maximum concentration: C

), ᭱ᑠ⾑୰⃰

ᗘ (minimum concentration: C

) ࡸ᭱㧗⾑୰⃰ᗘ฿㐩᫬㛫 (maximum drug concentration

time: T

) ࡣᚲࡎࡋࡶྠࡌ࡛ࡣ࡞࠸ . ≉࡟⤒ཱྀⓗ࡟ᢞ୚ࡉࢀࡿ⸆๣ࡢሙྜ࡟ࡣᾘ໬⟶྾཰

㐣⛬ࡢせᅉࡀቑ࠼ࡿࡓࡵ , ࡑࡢ᥇⾑࣏࢖ࣥࢺࡣ࡛ࡁࡿ㝈ࡾࡇࢀࡽࡢᙳ㡪ࡀᑡ࡞࠸᫬Ⅼࢆ㑅 ᢥࡍࡿࡇ࡜ࡀᮃࡲࡋ࠸ . ࡋ࠿ࡋ࡞ࡀࡽ , ࣋ࣉࣜࢪࣝ᭹⏝ᚋࡢ⾑₢୰⃰ᗘ᥎⛣࡟㛵ࡍࡿሗ࿌

ࡣᴟࡵ࡚ᑡ࡞࠸ .

ᅜෆ࡛ࡣ , ᮡࡽ

ࡀ」ᩘࡢ࣋ࣉࣜࢪࣝᢞ୚ᝈ⪅࡟࠾ࡅࡿ᭹⏝ᚋࡢ⾑

₢୰⃰ᗘࢆ ᐃࡋࡓ࡜ࡇࢁ , ᭹⏝ᚋࡢ⤒㐣᫬㛫࡟㛵ࢃࡽࡎ , ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ኱ࡁ ࡃኚ໬ࡋ࡞࠸ࡇ࡜ࢆሗ࿌ࡋ࡚࠸ࡿࡢࡳ࡛࠶ࡿ . ࡇࡢࡼ࠺࡟ , ᝈ⪅࡟࣋ࣉࣜࢪࣝࢆ⤒ཱྀᢞ୚

ࡋࡓ㝿ࡢ , ḟᅇᢞ୚ࡲ࡛ࡢ⾑₢୰⃰ᗘࢆ⤒᫬ⓗ࡟ ᐃࡋࡓሗ࿌ࡣ࡞ࡃ , ࣋ࣉࣜࢪࣝࡢ⮫ᗋ

ຠᯝ࡜⾑₢୰⃰ᗘࡢ㛵ಀࢆホ౯ࡍࡿࡓࡵࡢ㐺ษ࡞᥇⾑Ⅼࡣ᫂ࡽ࠿࡟ࡉࢀ࡚࠸࡞࠸ . ࡑࡇ࡛

ᮏ❶࡛ࡣ , Af ࡟ᑐࡋ࣋ࣉࣜࢪࣝ࡟ࡼࡿ⸆≀἞⒪ࢆ⾜ࡗ࡚࠸ࡿᝈ⪅ࡢ᭹⏝ᚋࡢ⾑₢୰⃰ᗘ᥎

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⛣ࢆ ᐃࡋ , ࣋ࣉࣜࢪࣝࡢ⾑₢୰⃰ᗘ࡜⮫ᗋຠᯝࡢ㛵ಀࢆ᫂☜࡟ࡍࡿࡓࡵࡢ᭱㐺࡞᥇⾑Ⅼ

ࢆ᥈⣴ࡍࡿࡇ࡜ࢆ┠ⓗ࡜ࡋࡓ . ࡲࡓ , 3 ྡࡢᝈ⪅ࢆᑐ㇟࡜ࡋ࡚ᚓࡽࢀࡓ⾑₢୰࣋ࣉࣜࢪࣝ

⃰ᗘ࡜⮫ᗋ⤒㐣ࢆẚ㍑ࡋ , ࡑࡢ᭷⏝ᛶ࡟ࡘ࠸࡚ホ౯ࡋࡓ .

➨ 2 ⠇ ᪉ἲ

1 㸧 ౑⏝⸆≀࠾ࡼࡧヨ⸆

➨ 1 ❶ , ➨ 2 ⠇ , ➨ 1 㡯 , 1) ࡟‽ࡌࡓ .

2 㸧 ᑐ㇟ᝈ⪅

ᮏ◊✲ࡣᕷ❧ᮐᖠ⑓㝔೔⌮ጤဨ఍ࡢᢎㄆࡢୗ࡟ , ᭩㠃࡟ࡼࡿᝈ⪅࠿ࡽࡢྠពࢆᚓࡓୖ࡛

⾜ࡗࡓ . ⤒ཱྀᢞ୚ᚋ , ḟᅇᢞ୚ࡲ࡛ࡢ⾑₢୰⃰ᗘ᥎⛣ࡢ᳨ウ࡛ࡣ , Af ࡢ἞⒪ࢆ┠ⓗ࡟ᕷ❧

ᮐᖠ⑓㝔ᚠ⎔ჾෆ⛉࡟ධ㝔ࡋࡓᝈ⪅ࡢ࠺ࡕ , ࣋ࣉࣜࢪࣝ᭹⏝ᚋ࡟⤒᫬ⓗ࡟᥇⾑ྍ⬟࡛࠶ࡗ ࡓ 3 ྡ㸦 2 ྡࡣ 1 ᪥ศ , 1 ྡࡣ 2 ᪥ศ : ⑕౛ 1 㹼 3 㸧ࢆᑐ㇟࡜ࡋࡓ . ᥇⾑Ⅼࡣ , ᢞ୚┤๓

࠾ࡼࡧᢞ୚ᚋ 12 ᫬㛫ࡲ࡛ࡢ 5 㹼 7 Ⅼ࡜ࡋࡓ . ᢞ୚┤๓࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡢ ಶయ㛫࠾ࡼࡧಶయෆኚືࡢ᳨ウ࡛ࡣ , ᐃᖖ≧ែ฿㐩ᚋ࡟」ᩘ᪥࡟ࢃࡓࡾᢞ୚┤๓ࡢ᥇⾑ࡀ

ྍ⬟࡛࠶ࡗࡓ 7 ྡ (6 ྡࡣ 2 ᪥ศ , 1 ྡࡣ 8 ᪥ศ㸸⑕౛ 4 㹼 10) ࢆᑐ㇟࡜ࡋࡓ . ᢞ୚┤๓

⃰ᗘ࡜⮫ᗋ⤒㐣࡟㛵ࡍࡿ᳨ウ࡛ࡣ , Af ࡟ࡼࡿᚰ㟁ᅗୖࡢ୙ṇ࡞ἼᙧࢆὝㄪᚊ໬ࡍࡿࡇ࡜ࢆ

┠ⓗ࡟ , ࣋ࣉࣜࢪࣝሷ㓟ሷỈ࿴≀㘄 (100 㹼 200 mg/day) ࡢ⤒ཱྀᢞ୚ࢆ㛤ጞࡋࡓᝈ⪅ 3 ྡ 㸦⑕౛ 11 㹼 13 㸧࡜ࡋࡓ . ᥇⾑ࡣࡍ࡭࡚ᢞ୚┤๓࡟⾜ࡗࡓ .

3 㸧 ㄪᰝ㡯┠

࣋ࣉࣜࢪࣝሷ㓟ሷỈ࿴≀㘄ࡢฎ᪉≧ἣ , ే⏝⸆≀ , Af ࡢฟ⌧㢖ᗘ , QT 㛫㝸 , ᚰᢿᩘ࡞࡝

ࡢ⮫ᗋᡤぢࡢ࡯࠿ , ࢔ࢫࣃࣛࢠࣥ㓟࢔࣑ࣀࢺࣛࣥࢫࣇ࢙࣮ࣛࢮ (aspartate amino transferase:

AST), ࢔ࣛࢽࣥ࢔࣑ࣀࢺࣛࣥࢫࣇ࢙࣮ࣛࢮ (alanine amino transferase: ALT), ⾑Ύࢡࣞ࢔ࢳ

ࢽࣥ (serum creatinine: Scr), ⾑୰ᒀ⣲❅⣲ (blood urea nitrogen: BUN) ࡞࡝ࡢ⫢ᶵ⬟࣭⭈ᶵ⬟

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᳨ᰝ್ࡣ࢝ࣝࢸࡼࡾㄪᰝࡋࡓ . ࡞࠾ , ࢡࣞ࢔ࢳࢽࣥࢡࣜ࢔ࣛࣥࢫ (creatinine clearance: Ccr) ࡣ Cockroft-Gault ᘧ

ࡼࡾ⟬ฟࡋࡓ .

Cockroft-Gault ᘧ㸸࠙⏨ᛶࠚ (140 㸫 Age) ™ Weight / (72 ™ Scr)

࠙ዪᛶࠚ (140 㸫 Age) ™ Weight ™ 0.85 / (72 ™ Scr)

Weight: kg, Scr: mg/dL

4 㸧 ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ ᐃἲ

➨ 1 ❶ , ➨ 2 ⠇ , ➨ 1 㡯 , 2), 3), 4) ࡟‽ࡌࡓ .

5 㸧 ᭷ຠᛶ࠾ࡼࡧ๪స⏝ุᐃ

SR ࠾ࡼࡧ Af, ᚰᡣ⢒ື (atrial flutter 㸸 AFL) ࡢุ᩿ࡣ་ᖌࡀ⾜࠸ , QT 㛫㝸ࡣ 12 ㄏᑟᚰ 㟁ᅗ࠿ࡽ ᐃࡋࡓ . ࡲࡓࠊ Yasuda ࡽࡢሗ࿌

࡟ᇶ࡙ࡁࠊ QT 㛫㝸ࡣ 0.52 ⛊௨ෆࢆチᐜ⠊

ᅖ࡜ࡋࡓࠋ

➨ 3 ⠇ ⤖ᯝ

➨ 1 㡯 ࣋ࣉࣜࢪࣝ⤒ཱྀᢞ୚ᚋࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ᥎⛣࡜᥇⾑Ⅼࡢጇᙜᛶ

1 㸧 ࣋ࣉࣜࢪࣝ⤒ཱྀᢞ୚ᚋࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘ᥎⛣

࣋ࣉࣜࢪࣝ᭹⏝ᚋ 5 㹼 12 ᫬㛫ࡲ࡛⤒᫬ⓗ࡟᥇⾑ࡋࡓ 3 ⑕౛࡟࠾ࡅࡿ⾑₢୰⃰ᗘ᥎⛣ࢆ

Fig. 6 ࡟♧ࡋࡓ . ⑕౛ 1 ࡛ࡣᢞ୚┤๓࠾ࡼࡧ 1 ᅇ 50 mg (100 mg/day, 1 ᪥ 2 ᅇ ) ࡟࡚⤒ཱྀ

ᢞ୚ᚋ , 1 㹼 12 ᫬㛫ᚋࡢィ 7 Ⅼࡢ⾑₢୰⃰ᗘࢆᚓࡓ . ᢞ୚┤๓ࡢ⾑₢୰⃰ᗘࡣ 197 ng/mL

࡛࠶ࡗࡓࡀ , ᢞ୚ 2 ᫬㛫ᚋ࡟ࡣ 167 ng/mL ࡟పୗࡋࡓ . ࡑࡢᚋ , ⾑₢୰⃰ᗘࡣୖ᪼ࡋ , ᢞ

୚ 6 ᫬㛫ᚋ࡟ 273 ng/mL ࡜࡞ࡗࡓᚋ࡟෌ࡧῶᑡࡋ , ᭹⏝ 12 ᫬㛫ᚋ࡟ࡣᢞ୚┤๓࡜ྠࣞ

࣋ࣝ࡜࡞ࡗࡓ (Fig. 6A).

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⑕౛ 2 ࡛ࡣᢞ୚┤๓࠾ࡼࡧ , 1 ᅇ 100 mg (200 mg/day, 1 ᪥ 2 ᅇ ) ࡟࡚⤒ཱྀᢞ୚ᚋ , 0.5 㹼 8.5 ᫬㛫ᚋࡢィ 6 Ⅼ࡟࠾ࡅࡿ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࢆᚓࡓ . ࡞࠾ , ᮏ⑕౛ࡣ࣋ࣉࣜࢪࣝ

ᢞ୚┤ᚋ࠿ࡽ 4.5 ᫬㛫ᚋࡲ࡛㏱ᯒࢆ᪋⾜ࡋ࡚࠸ࡓ . ᢞ୚┤๓ࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ 132 ng/mL ࡛࠶ࡗࡓࡀ , ᢞ୚ 0.5 ᫬㛫ᚋ࡟ࡣ 117 ng/mL ࡟పୗࡋࡓ . ࡑࡢᚋ , ㏱ᯒ⤊஢┤

๓࡛࠶ࡿ 4.5 ᫬㛫ᚋ࡟ 346 ng/mL ࡲ࡛ୖ᪼ࡋ , ࡑࡢᚋ෌ࡧῶᑡࡋࡓ (Fig. 6B).

⑕౛ 3 ࡣ㏱ᯒ᪥࠾ࡼࡧ㠀㏱ᯒ᪥ࡢ 2 ᪥㛫࡟ , ᢞ୚┤๓࠾ࡼࡧ , 1 ᅇ 50 mg (150 mg/day, 1 ᪥ 3 ᅇ ) ࡟࡚⤒ཱྀᢞ୚ᚋ 4.5 ᫬㛫ࡲ࡛ࡢྛ 5 Ⅼࢆᚓࡓ . 㠀㏱ᯒ᪥࡛ࡣᢞ୚┤๓ࡢ⾑₢୰

࣋ࣉࣜࢪࣝ⃰ᗘࡣ 629 ng/mL ࡛࠶ࡗࡓࡀ , ᢞ୚┤ᚋ࠿ࡽࡍࡳࡸ࠿࡟⾑₢୰⃰ᗘࡣୖ᪼ࡋ ,

᭹⏝ 2.5, 3.5 ᫬㛫ᚋ࡟ࡑࢀࡒࢀ 829, 834 ng/mL ࡜࡞ࡾ , ࡑࡢᚋ , ῶᑡࡋࡓ (Fig. 6C). ୍᪉ ,

㏱ᯒ᪥࡛ࡣᢞ୚┤๓ࡢ⾑₢୰࣋ࣉࣜࢪࣝ⃰ᗘࡣ 788 ng/mL ࡛࠶ࡗࡓࡀ , ᢞ୚ 2.5 ᫬㛫ᚋ࡟

ࡣ 743 ng/mL ࡜࡞ࡗࡓᚋ࡟ୖ᪼ࡋ , ᢞ୚ 4.5 ᫬㛫ᚋ࡟ࡣ 931 ng/mL ࡜࡞ࡗࡓ (Fig. 6D).