Cisplatin metabolites

BCRP (ABCG2) Cisplatin, folate, methotrexate, mitoxantrone, topotecan, irinotecan, steroids (cholesterol, testosterone, progesterone), certain chlorophyll metabolites, and others... 

The chelated square-planar metabolite [Pt(Met)2)l has been detected in urine of patients treated with cisplatin (89). It is a relatively unreactive complex, existing in solution as a mixture of three diaster-eoisomers of each of the two geometrical isomers (90). The cis isomer predominates over the trans isomer by 87 13, and interconversion is slow (half-lives for conversion of cis to trans 22.4 h and of trans to cis 3.2 h at 310 K). 

K. Hanada, K. Ninomiya, H. Ogata, Pharmacokinetics and Toxicodynamics of Cisplatin and Its Metabolites in Rats Relationship between Renal Handling and Nephrotoxicity of Cisplatin , J. Pharm. Pharmacol. 2000, 52, 1345 - 1353. 

Most platinum compounds exist as coordination complexes the tetravalent compounds typically are more toxic than the hexavalent ones [10]. Certain neutral platinum complexes exhibit antitumor activity and therefore are used in chemotherapy drugs such as cisplatin. Speeiation is required to distinguish platinum chemotherapy drugs from their metabolites in patients blood and serum samples. 

Platinum speciation using IPC-ICP-MS has been achieved by Zhao et al. [50], An ODS C18 column and 1-heptanesulfonate ion-pairing reagent at pH 2.6 were used to separate the metabolites of cisplatin and cisplatin hydrolysis products. The low pH was required in order to retain thiol containing complexes. All complexes were resolved and urine and blood samples were analyzed by the speciation method. 

Interpretation of pharmacokinetic data is also complicated by biotransformation processes. Cisplatin is metabolized to various aquated species and in the low-chloride intracellular environment these predominate. Plati-num(IV) compounds are converted rapidly to platinum(II) derivatives in plasma, and multiple distinct circulating molecular species may be produced [223], While some HPLC assays may distinguish among metabolites, sensitivity often limits resolution of the various molecular species. Pharmacokinetic data should be interpreted accordingly. Recently it has been possible... 

Fig. 11.195Pt-NMR Spectrum of I Pt(, -I5N-Met)2], a metabolite of the cisplatin, showing three sets of triplets for each of the cis- and ir ns-isomers. The three diastereomers for each geometrical isomer arise from slow inversion (on the NMR time scale) of chiral coordinated sulfur. (Adapted from [29]).

Fig. 3. Cross-resistance profiles for the 41M/41McisR, CH 1/CH1 c sR and A2 780/A2780cisR pairs of human ovarian-carcinoma cell lines for cisplatin itself carboplatin, tetraplatin (1,2-diaminocyclohexane)tetrachloroplatinum(IV)), JM216, JM118 (the major metabolite of JM216) andAMD473. Resistance Factor = IC50 resistant/parent cell line. Drug exposure was for 96 h, sulforhodamine B growth-inhibition assay, bars = SEM, n = 3-4.

Thioethers form stable complexes, particularly if they are polydentate. Whereas only two sulfur atoms are coordinated in Ph2Pt(9S3),26 larger macrocycles, as in [Pt(12S4)]2+, can encapsulate the metal atom.27 The L-methionine complex (18-H-XII) is a metabolite of the anti-cancer drug cisplatin (see below).28... 

Black cohosh 2. Geum chiloense 3. Liquorice 1. Cisplatin 2. Azathioprine 3. Cidosporin 4. Prednisolone t cytotoxic properties. Geum t plasma cidosporin levels 6-8-fold Unknown mechanism (black cohosh) Inhibits metabolizing enzymes. Glycyrrhizin present in liquorice inhibits the metabolizing enzyme of prednisolone, 11 beta-hydroxysteroid dehydrogenase, which converts the active metabolite to an inactive form. i clearance of prednisolone in healthy individuals Be aware. Advice is to avoid echinacea with immunosuppressants... 

Nygren, Y., Hemstrdm, P., Astot, C., Naredi, P., Bjorn, E. Hydrophilic interaction liquid chromatography (HILIC) coupled to inductively coupled plasma mass spectrometry (ICPMS) utilizing a mobile phase with a low-volatile organic modifier for the determination of cisplatin, and its monohydrolyzed metabolite. J. Anal. At. Spectrom. 23, 948-954 (2008)... 

Huang, Z., Timerbaev, A.R., Keppler, B.K., Hirokawa, T. Determination of cisplatin and its hydrolytic metabolite in human serum by capillary electrophoresis techniques. J. Chromatogr. A 1106, 75-79 (2006)... 

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