Pharmacokinetics and Toxicities of Cisplatin Among Bangladeshi Cancer Patients and Measures to Reduce the Toxicity

Abstract

Background: Cisplatin, an old chemotherapeutic agent used to treat various types of cancers, including sarcomas, some carcinomas e.g. small cell lung cancer and ovarian cancer, lymphomas and germ cell tumors etc. Most important toxicity of cisplatin is nephrotoxicity produced by cisplatin itself and its few metabolites, which are some time fatal, various attempt were taken to risk reduction previously, use of the medicinal plant materials was the new concept, such as extract of D.alata and M. olifera which was proved promising activity in this study. Methods: 250 blood samples corresponding 250 urine samples of 50 adult cancer patients admitted in the IPD of KYAMC Cancer Centre, Khwaja Yunus Ali Medical College, Enayetur, Sirajgonj were collected at 0 (predose), 3, 6, 12 and 24 hour and placed in HPLC for identifying the RT and Area of Cisplatin and its possible metabolites and their concentrations in plasma and urine at different time interval, where nickel chloride used as internal standard. For isolation and purification of cisplatin and its possible metabolites 24 hours urine of 5 patients were collected and were placed in long chromatographic procedure such as column chromatography, glass chromatography, thin layer chromatography gave rise to 5 single compounds which was detected under UV spectrometry. Cytotoxicy of 5 compounds were done by using brine shrimp lethality bioassay. D. alata and M. olifera extracts were applied the cisplatin and its metabolites induced nephrotoxicity in mice and histo-pathological slides were prepared from the liver and kidney of mice to see the pathological. A series of pathological & biochemical investigations of blood and urine, various images technique of 50 patients were done. The data were statistically analyzed by ANOVA (one way of analysis of varience) and post-hoc Dunnett’s tests the Statistical Package for Social Sciences (SPSS 16.0, USA) program.

Result & Discussion: A potent anti-cancer drug, cisplatin, used in various types of malignancies, but its use is limited due to it produce nephrotoxicity. 50 male patients treated with cisplatin in IPD of Khwaja Yunus Ali Medical College Cancer Centre (KYAMC Cancer Centre) on Sirajgonj showed most vulnerable age group 53-60 years 56% (n=28), moderate to severe anemic 2% (n=1), moderate to severe jaundice 4% (n=2), about 8% (n=4) were suffered from edema, Moderate increased of serum creatinine (μg/dl), blood urea (μg/dl) and albuminurea levels were found as 28% (n=14), 20% (n=10) and 32% (n=16) of the total patients respectively, strongly suggesting that cisplatin or its metabolites produced nephrotoxicities. From the evidence of HPLC data sheet, four suspected metabolites (CM2, CM3, CM4 and CM5) were identified with their specific RT (retention time) and Area, where mean plasma concentration of one suspected metabolite CM2 was gradually increased highest level to 234.64 μg/dl (±6.30) after 12 hours (p>0.01) indicating the finding not significant and its corresponding urine concentration highest after 24 hour were 269.43 μg/dl (±6.98) indicating the findings significant (p<0.001), for another metabolite CM5 was found after 3 hour to minimum to 8.02 μg/dl (±8.75) which was sharply increased to 53. 86 (±2.73) after 12 hours then gradually decreased to 39.06 μg/dl (±5.44) after 24 hours (p>0.01). Among 50 patients about 28% (n=14), 16% (n=8) & 20% (n=10) of the patient suffered increased serum creatinine level, increased albuminuria and increased blood urea level respectively. Primary screening for cytotoxicity of these five compounds (C, CM2, CM3, CM4 and CM5) along with cisplatin (as standard solution) were done by using brine shrimp lethality bioassay (figure 20-25 & table 4-9). Among them, comparative to cisplatin, its metabolites are more toxic, specially CM2 (Meta2, LC50=1.2μgm/ml), CM3 (Meta 3, LC50=1.08μgm/ml) and CM4 (Meta 4, LC50=1.182μgm/ml)

which was correlate to the previous study indicating the findings significant (p >0.01). A promising results showed that the use of some medicinal plant extracts (D. alata and Morienga olifera) gave rise to moderate restoration of normal physiology of kidney and liver of mice. The effects of the methanolic extracts of D. alata and Morienga olifera on biochemical parameter in mice also observed and found significant decrease in blood urea and creatinine levels and increase activity of GSH in all experimental mice groups which is proven antioxidant and nephroprotective. Conclusion: Metabolites of Cisplatin induced nephrotoxicity was more prominent than cisplatin in our study. After adequate hydration of the admitted cancer patients in Khwaja Yunus Ali Medical College they were suffer nephrotoxicities. Extracts of D. alata and Morienga olifera had some effects on biochemical parameters; its effect on renal histology in injured mice kidney was very promising and significant. -