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High-pH or basic/alkaline mobile phases are not commonly used in LC-MS or LC-MS/MS bioanalysis because of the deeply rooted concern with column instability and reduced detection sensitivity for basic compounds in high-pH mobile phases owing to charge neutralization. With the advancement of LC column technology and the wide recognition of the "wrong-way-round" phenomena, high-pH mobile phases are more and more used in LC-MS or LC-MS/MS bioanalysis to improve chromatographic peak shape, retention, selectivity, resolution, and detection sensitivity, not only for basic compounds, but also for many other compounds. In this article, the benefits, practical considerations, application examples and cautions for using high-pH mobile phases in LC-MS or LC-MS/MS bioanalysis are reviewed, with a focus on quantification. Furthermore, the future trends in this field are also envisaged.A total of 84 references are cited in this review. KEYWORDS alkaline mobile phase, basic mobile phase, bioanalysis, high pH, LC-MS, LC-MS/MS

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Diabetic retinopathy is a major cause of vision loss in adults. Novel eye-drop formulations of candesartan and irbesartan are being developed for its cure or treatment. To support a preclinical trial in rabbits, it was critical to develop and validate a new LC-MS/MS method for simultaneous quantification of candesartan and irbesartan in rabbit eye tissues (cornea, aqueous humor, vitreous body and retina/choroid). Eye tissue samples were first homogenized in H 2 O-diluted rabbit plasma. The candesartan and irbesartan in the supernatants together with their respective internal standards (candesartan-d 4 and irbesartan-d 4 ) were extracted by solid-phase extraction. The extracted samples were injected onto a C 18 column for gradient separation. The MS detection was in the positive electrospray ionization mode using the multiple reaction monitoring transitions of m/z 441 ! 263, 445 ! 267, 429 ! 207, and 433 ! 211 for candesartan, candesartan-d 4 , irbesartan and irbesartan-d 4 , respectively. For the validated concentration ranges (2-2000 and 5-5000 ng/g for candesartan and irbesartan, respectively), the within-run and between-run accuracies (% bias) were within the range of −8.0-10.0. The percentage CV ranged from 0.6 to 7.3. There was no significant matrix interference nor matrix effect from different eye tissues and different rabbits. The validated method was successfully used in the Good Laboratory Practice (GLP) study of rabbits. K E Y W O R D S candesartan, eye tissue, irbesartan, LC-MS, rabbit