Validation and use of three complementary analytical methods (LC-FLS, LC-MS/MS and ICP-MS) to evaluate the pharmacokinetics, biodistribution and stability of motexafin gadolinium in plasma and tissues.
Liquid chromatography-fluorescence (LC-FLS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) methods were developed and validated for the evaluation of motexafin gadolinium (MGd, Xcytrin) pharmacokinetics and biodistribution in plasma and tissues. The LC-FLS method exhibited the greatest sensitivity (0.0057 microg mL(-1)), and was used for pharmacokinetic, biodistribution, and protein binding studies with small sample sizes or low MGd concentrations. The LC-MS/MS method, which exhibited a short run time and excellent selectivity, was used for routine clinical plasma sample analysis. The ICP-MS method, which measured total Gd, was used in conjunction with LC methods to assess MGd stability in plasma. All three methods were validated using human plasma. The LC-FLS method was also validated using plasma, liver and kidneys from mice and rats. All three methods were shown to be accurate, precise and robust for each matrix validated. For three mice, the mean (standard deviation) concentration of MGd in plasma/tissues taken 5 hr after dosing with 23 mg kg(-1) MGd was determined by LC-FLS as follows: plasma (0.025+/-0.002 microg mL(-1)), liver (2.89+/-0.45 microg g(-1)), and kidney (6.09+/-1.05 microg g(-1)). Plasma samples from a subset of patients with brain metastases from extracranial tumors were analyzed using both LC-MS/MS and ICP-MS methods. For a representative patient, > or = 90% of the total Gd in plasma was accounted for as MGd over the first hour post dosing. By 24 hr post dosing, 63% of total Gd was accounted for as MGd, indicating some metabolism of MGd.
Miles
Dale R
DR
Pharmacyclics, Inc., 995 E. Arques Avenue, Sunnyvale, CA 94085, USA. dmiles@pcyc.com
Mesfin
Mimi
M
Mody
Tarak D
TD
Stiles
Mark
M
Lee
Jean
J
Fiene
John
J
Denis
Bernie
B
Boswell
Garry W
GW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002624:Chemistry, Clinical / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods*; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods*; D008665:Metalloporphyrins / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D008956:Models, Chemical; D051381:Rats; D012680:Sensitivity and Specificity; D013997:Time Factors
D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C437683:motexafin gadolinium