In vivo and ex vivo magnetic resonance spectroscopy as applied to pharmacokinetic studies with anticancer agents: a review

Abstract

The potential role of MRS in studying the pharmacokinetics of anticancer drugs is reviewed. In vivo and ex vivo MRS has been used extensively in studies with fluoropyrimidines. Results from preclinical models have demonstrated that biochemical modulation of 5-fluorouracil metabolism can be demonstrated by MRS. The more general potential of MRS is illustrated by studies with the antifolate CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid). Studies in mice and rats have shown that hepatobiliary clearance and renal elimination can be measured non-invasively by MRS. Comparison of half-lives derived from MRS and high performance liquid chromatography data gave reasonable agreement. In addition, MRI was used to localize drug-derived material within the abdominal cavity. The application of ex vivo MRS is illustrated by studies on the urinary excretion of platinum complexes. 1H-MRS has been used to demonstrate the presence of the cyclobutanedicarboxylate leaving group, both free and platinum bound, in the urine of patients treated with carboplatin. With iproplatin 195Pt NMR has been used to demonstrate in vivo reduction of this Pt(IV) complex to Pt(II) complexes. Finally, the application of MRS to the study of the molecular pharmacology of alkylating agents (a nitrogen mustard and N-methyl-N-nitrosourea) is discussed.

Monitoring Local Disposition Kinetics of Carboplatinin Vivoafter Subcutaneous Injection in Rats by Means of195Pt NMR

“…A large number of 195 Pt NMR studies on solutions followed (reviews, see Refs. 8,9,10). For example, investigations of the interaction of cisplatin with singleand double-stranded DNA in vitro by means of 195 Pt NMR (11) showed stable intrastrand crosslinks with the N 7 -position of purine bases producing an unwinding of DNA by 13 to 23 degrees (as detected by means of 2D 1 H NMR and gel electrophoresis (12,13)).…”

Non‐invasive MRS in new anticancer drug development

“…' Since the presence of fluorine in a molecule presents an exceptional opportunity to study pharmacokinetics non-invasively by ' % MRS (see.Ref. 4) we decided to apply this to /?,/?-diff uorochlorambucil.…”

Phosphorous metabolites and steady-state energetics of transformed fibroblasts during three-dimensional growth

“…energy metabolism; tumor biology; nuclear magnetic resonance spectroscopy; phospholipids; quiescence MAGNETIC RESONANCE SPECTROSCOPY (MRS) is increasingly utilized as an in vivo method to monitor cell metabolism and tissue oxygenation in various organs and diseases (17,27,41,49). New approaches include its application in neuropsychiatric and toxicology research (5, 10, 46, 61), and it is widely applied in pharmacokinetic and comparative physiological studies (47,50,56,67,84). MRS has also become a powerful technological tool providing noninvasive access to tumor bioenergetic state because of its most attractive feature of nondestructively measuring chemical compounds in intact, living tissues (17, 27).…”

“…New approaches include its application in neuropsychiatric and toxicology research (5,10,46,61), and it is widely applied in pharmacokinetic and comparative physiological studies (47,50,56,67,84). MRS has also become a powerful technological tool providing noninvasive access to tumor bioenergetic state because of its most attractive feature of nondestructively measuring chemical compounds in intact, living tissues (17,27).…”