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CHI TIẾT
Nghiên cứu định lượng rosuvastatin trong huyết tương người bằng phương pháp sắc ký lỏng – khối phổ
Quantification of rosuvastatin in human plasma by liquid chromatography electrospray ionization mass spectrometry
Tạ Mạnh Hùng, Phan Thị Nghĩa, Nguyễn Thị Dung, Nguyễn Thị Thu Hòa
Số: 521 - Tháng 9/2019 - Trang 22-27

Rosuvastatin (C22H28FN3O6S, KLPT: 481,5 g/mol) là thuốc chỉ định trong điều trị tăng cholesterol máu và rối loạn lipid máu. Do nồng độ đỉnh (Cmax) của rosuvastatin trong huyết tương người sau khi uống một liều đơn 10 mg dược chất tương đối thấp (khoảng 15 ng/ml), nên việc xác định nồng độ rosuvastatin trong các mẫu huyết tương người đòi hỏi phải có phương pháp chiết tách phù hợp và phương pháp phân tích có độ nhạy cao. Dựa vào trang thiết bị hiện có và tham khảo một số phương pháp phân tích đã được các tác giả công bố đồng thời dựa trên nguyên lý hoạt động của phương pháp sắc ký lỏng - khối phổ, đã tiến hành nghiên cứu định lượng rosuvastatin trong huyết tương người bằng phương pháp sắc ký lỏng với detector khối phổ kiểu tứ cực chập ba (LC-MS/MS). Phương pháp phân tích sẽ được áp dụng trong các nghiên cứu sinh khả dụng và tương đương sinh học thuốc generic chứa dược chất rosuvastatin.

Đối tượng nghiên cứu

Các mẫu huyết tương người chứa dược chất cần phân tích rosuvastatin.

Chất chuẩn: Rosuvastatin của Viện Kiểm nghiệm thuốc TP. Hồ Chí Minh, glibenclamid.

Dung môi, hóa  chất: Đạt tiêu chuẩn dùng cho HPLC và LC/MS.

Huyết tương trắng: Không có rosuvastatin của Viện Huyết học và Truyền máu Trung ương.

Thiết bị và dụng cụ phân tích: Các thiết bị phân tích được quản lý và hiệu chuẩn theo các quy định của ISO/IEC 17025 và GLP bao gồm máy sắc ký lỏng khối phổ TSQ Quantum Vantage, cân phân tích, độ chính xác d = 0,01 mg. Tủ lạnh sâu -35 oC ± 5 oC, máy ly tâm lạnh, máy lọc nước, micropipet và các dụng cụ thủy tinh cần thiết.

Phương pháp nghiên cứu

Dựa trên các tính chất hóa lý của rosuvastatin ít tan trong nước, tan được trong một số dung môi không phân cực và có tính acid yếu nghiên cứu phương pháp chiết lỏng – lỏng với các hệ dung môi khác nhau để xử lý, chiết tách dược chất từ các mẫu huyết tương có nền mẫu phức tạp.

Nghiên cứu các điều kiện sắc ký lỏng và điều kiện phổ khối phù hợp để định lượng rosuvastatin (ROSU) trong các mẫu huyết tương đã được xử lý chiết tách dược chất cần phân tích bằng phương pháp chiết lỏng – lỏng thích hợp đã nghiên cứu được. Xác định nồng độ ROSU có trong các mẫu thử (chưa biết nồng độ) dựa vào tỷ lệ diện tích pic ROSU/IS (IS là nội chuẩn glibenclamid) thu được từ sắc đồ của mẫu thử và đường chuẩn biểu thị mối tương quan giữa nồng độ ROSU có trong các mẫu chuẩn với tỷ lệ diện tích pic ROSU/IS của mẫu chuẩn.

Tiến hành thẩm định độ đặc hiệu - chọn lọc, giới hạn định lượng dưới, độ đúng, độ chính xác, tỷ lệ thu hồi hoạt chất, ảnh hưởng của nền mẫu, độ ổn định ... của phương pháp theo các hướng dẫn thẩm định phương pháp định lượng thuốc trong dịch sinh học của US-FDA và EMA.

Kết luận

Đã xây dựng được phương pháp định lượng rosuvastatin trong huyết tương người bằng phương pháp LC-MS/MS. Kết quả thẩm định cho thấy, phương pháp có giá trị giới hạn định lượng dưới nhỏ (0,3 ng/ml); khoảng tuyến tính rộng (từ 0,3 ng/ml đến 30 ng/ml); độ đúng dao động trong khoảng 93,7%-110,5%; độ lặp lại với giá trị CV% nhỏ (3,6%-14,3%), đáp ứng yêu cầu đối với phương pháp phân tích thuốc trong dịch sinh học của US-FDA và EMA. Phương pháp đã xây dựng có thể ứng dụng trong các nghiên cứu sinh khả dụng và đánh giá tương đương sinh học đối với chế phẩm chứa hoạt chất rosuvastatin.

A liquid chromatography-electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) was developed and validated for identification and quantification of rosuvastatin in human plasma. Rosuvastatin and glibenclamid (internal standard) were isolated from plasma samples by liquid-liquid extraction with methyl-tert-butyl ether. The chromatographic separation was accomplished on a Acquity C18 column (2.1 x 100 mm; 1.7 µm particle size) with the mobile phase consisting of acetonitrile and ammonium formate buffer solution pH 3.5  (90:10, v/v), and the flow rate was 0.2 ml/min. Detection was performed on a triple quadruple mass spectrometer by selected reaction monitoring (SRM) mode (m/z:  482.5 à 258.2 for rosuvastatin and m/z: 494.0 à 368.9 for internal standard); the retention time was about 1.6 and 1.8 min, respectively. The calibration curve for rosuvastatin was satisfactory with regression coefficient 0.995 over the range of 0.3–30 ng/ml (in the plasma). Accordingly, the LOQ (S/N > 10) was 0.3 ng/ml. The intra-day and inter-day precision expressed as relative standard deviation was 3.6–14.3% and 5.9–12.2%. Validated according to the guidelines for validation of bioanalytical methods by FDA and EMA, the proposed method proved reliable and practicable, and as such, useful for BA-BE studies of rosuvastatin preparations.

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