Simultaneous determination of myristyl nicotinate, nicotinic acid, and nicotinamide in rabbit plasma by liquid chromatography–tandem mass spectrometry using methyl ethyl ketone as a deproteinization solvent
Catz, Paul
(Toxicology and Metabolism Laboratory, SRI International, 333 Ravenswood Ave. Menlo Park, CA 94025, USA)
,
Shinn, Walter
(Toxicology and Metabolism Laboratory, SRI International, 333 Ravenswood Ave. Menlo Park, CA 94025, USA)
,
Kapetanovic, Izet M.
(Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Executive Plaza North, Room 2116, 6130 Executive Blvd., Bethesda, MD 20892-7322, USA)
,
Kim, Hyuntae
(Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA)
,
Kim, Moonsun
(Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA)
,
Jacobson, Elaine L.
(Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA)
,
Jacobson, Myron K.
(Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA)
,
Green, Carol E.
(Toxicology and Metabolism Laboratory, SRI Inter)
AbstractMyristyl nicotinate (Nia-114) is an ester prodrug being developed for delivery of nicotinic acid (NIC) into the skin for prevention of actinic keratosis and its progression to skin cancer. To facilitate dermal studies of Nia-114, a novel liquid chromatography–tandem mass spectrometry (...
AbstractMyristyl nicotinate (Nia-114) is an ester prodrug being developed for delivery of nicotinic acid (NIC) into the skin for prevention of actinic keratosis and its progression to skin cancer. To facilitate dermal studies of Nia-114, a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) method using methyl ethyl ketone (MEK) as a deproteinization solvent was developed and validated for the simultaneous determination of Nia-114, NIC, and nicotinamide (NAM) in rabbit plasma. NAM is the principal metabolite of NIC, which is also expected to have chemopreventive properties. The analytes were chromatographically separated using a Spherisorb Cyano column under isocratic conditions, and detected by multiple reaction monitoring (MRM) in positive-ion electrospray ionization mode with a run time of 9min. The method utilized a plasma sample volume of 0.2ml and isotope-labeled D4 forms of each analyte as internal standards. The method was linear over the concentration range of 2–1000, 8–1000, and 75–1000ng/ml, for Nia-114, NIC, and NAM, respectively. The intra- and inter-day assay accuracy and precision were within ±15% for all analytes at low, medium, and high quality control standard levels. The relatively high value for the lower limit of quantitation (LLOQ) of NAM was demonstrated to be due to the high level of endogenous NAM in the rabbit plasma (about 350ng/ml). Endogenous levels of NIC and NAM in human, dog, rat, and mouse plasma were also determined, and mean values ranged from <2ng/ml NIC and 38.3ng/ml NAM in human, to 233ng/ml NIC and 622ng/ml NAM in mouse. Nia-114 was generally unstable in rabbit plasma, as evidenced by loss of 44–50% at room temperature by 2h, and loss of 64–70% upon storage at −20°C for 1 week, whereas it was stable (<7% loss) upon storage at −80°C for 1 month.
AbstractMyristyl nicotinate (Nia-114) is an ester prodrug being developed for delivery of nicotinic acid (NIC) into the skin for prevention of actinic keratosis and its progression to skin cancer. To facilitate dermal studies of Nia-114, a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) method using methyl ethyl ketone (MEK) as a deproteinization solvent was developed and validated for the simultaneous determination of Nia-114, NIC, and nicotinamide (NAM) in rabbit plasma. NAM is the principal metabolite of NIC, which is also expected to have chemopreventive properties. The analytes were chromatographically separated using a Spherisorb Cyano column under isocratic conditions, and detected by multiple reaction monitoring (MRM) in positive-ion electrospray ionization mode with a run time of 9min. The method utilized a plasma sample volume of 0.2ml and isotope-labeled D4 forms of each analyte as internal standards. The method was linear over the concentration range of 2–1000, 8–1000, and 75–1000ng/ml, for Nia-114, NIC, and NAM, respectively. The intra- and inter-day assay accuracy and precision were within ±15% for all analytes at low, medium, and high quality control standard levels. The relatively high value for the lower limit of quantitation (LLOQ) of NAM was demonstrated to be due to the high level of endogenous NAM in the rabbit plasma (about 350ng/ml). Endogenous levels of NIC and NAM in human, dog, rat, and mouse plasma were also determined, and mean values ranged from <2ng/ml NIC and 38.3ng/ml NAM in human, to 233ng/ml NIC and 622ng/ml NAM in mouse. Nia-114 was generally unstable in rabbit plasma, as evidenced by loss of 44–50% at room temperature by 2h, and loss of 64–70% upon storage at −20°C for 1 week, whereas it was stable (<7% loss) upon storage at −80°C for 1 month.
Seee http://www.fda.gov/cder/guidance/4252fnl.htm Guidance for Industry, Bioanalytical Method Validation, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), BP, May 2001.
J. Chromatogr. B Iwaki 747 229 2000 10.1016/S0378-4347(99)00486-7
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