Oxaliplatin degradation in the presence of important biological sulphur-containing compounds and plasma ultrafiltrate.
Oxaliplatin undergoes extensive non-enzymatic chemical transformation in the body. Complexes with sulphur-containing compounds have previously been found in plasma from patients treated with oxaliplatin. We have studied the kinetics for the reactions between oxaliplatin and cysteine, methionine, and glutathione, by determination of the degradation of oxaliplatin using liquid chromatography with UV-detection. We also studied the degradation of oxaliplatin in plasma ultrafiltrate (PUF). For the degradation of oxaliplatin in the presence of glutathione, methionine, and cysteine, the second-order rate constants were 4.7M(-1)min(-1) (95% confidence interval [C.I.], 4.4-5.0M(-1)min(-1)), 5.5M(-1)min(-1) (95% C.I., 5.2-5.7M(-1)min(-1)), and 15M(-1)min(-1) (95% C.I., 14-17M(-1)min(-1)), respectively. The reaction rate was much faster than previously reported kinetics for cisplatin. The degradation rate of oxaliplatin in PUF was biphasic. The rate constant for the first phase varied from 9.5x10(-3) to 0.13min(-1) and for the second phase from (1.7 to 1.8)x10(-3)min(-1) in PUF from five healthy volunteers. The first hours of the degradation of oxaliplatin in PUF are accounted for by the degradation of oxaliplatin in a cocktail of sodium chloride and sulphur-containing compounds at physiological plasma concentrations. In conclusion, the rate of the reaction of oxaliplatin with three sulphur-containing compounds was faster for oxaliplatin than what is previously known for cisplatin. This may be important with respect to differences in the cellular effects of cisplatin and oxaliplatin treatment.
Jerremalm
Elin
E
Karolinska Pharmacy, Karolinska University Hospital, S-171 76 Stockholm, Sweden. elin.jerremalm@telia.com
Wallin
Inger
I
Yachnin
Jeffrey
J
Ehrsson
Hans
H
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D003545:Cysteine / Q000737:chemistry*; D004355:Drug Stability; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008715:Methionine / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D000077150:Oxaliplatin; D010949:Plasma / Q000737:chemistry / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D014462:Ultrafiltration
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D008715:Methionine; D005978:Glutathione; D003545:Cysteine