Quantitation of motexafin lutetium in human plasma by liquid chromatography-tandem mass spectrometry and inductively coupled plasma-atomic emission spectroscopy.
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected into an LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 microg MLu mL(-1), with a signal-to-noise ratio of 15:1. The response was linear from 0.05 to 5.0 microg MLu mL(-1). For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected into the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 microg Lu mL(-1). The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples were < or =6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, and < or =8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred.
Miles
Dale
D
Pharmacyclics, Inc, Sunnyvale, CA 94085-4521, USA.
Mody
Tarak D
TD
Hatcher
Lori I
LI
Fiene
John
J
Stiles
Mark
M
Lin
Patrick P
PP
Lee
J W
JW
D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D008665:Metalloporphyrins / Q000097:blood*; D015203:Reproducibility of Results; D013054:Spectrophotometry, Atomic / Q000379:methods*
D008665:Metalloporphyrins; C102825:motexafin lutetium