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Oxaliplatin: Investigation of Safety in Heated Intra-peritoneal Perfusion and Pharmacokinetic Study

Author: SongXiaoKun
Tutor: LouJianShi
School: Tianjin Medical University
Course: Pharmacology
Keywords: L-OHP HPLC heated intra-operative intra-peritoneal therapy blood drug level blood-proteins bounding rate pharmacokinetic parameters colorectal cancer stability
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 135
Quote: 1
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Abstract

Objective: To establish the determination method of L-OHP in vivo and in vitro by HPLC, to considerate the security of L-OHP administrating in heated intra-operative intra-peritoneal therapy of digestive system neoplasm’s patients. To analysis pharmacokinetic parameters between difference dosage in two regimens by intravenous infusion, and monitoring the changes of platinum bounding with blood-proteins in vivo.Method:1. To determine the stability of oxaliplatin （L-OHP） for injection in different dosages （85mg/m² and 130mg/m²） at 42℃in heated intra-operative intra-peritoneal therapy; To determine the compatibility of L-OHP and lidocaine/procaine/ dexamethasone at two temperature （25℃and 42℃）. To determine the concentration of L-OHP in peritoneal cavity fluids in 24h.The Kromasil C-18 column （250mm×4.6mm,5μm） was used. The mobile phase consisted of methanol-water （7:93）, the flow rate was 1ml/min, the detection wavelength was at 249nm, the sample size was 20μl and the column temperature was at the room temperature.2. The HPLC-UV assay of L-OHP in serum was developed and NiCl₂ was used as internal standard and DDTC was used as derivative. Ultracentrifugation method was used to determine concentration of free-platinum in serum, and reforming acidic proteopepsis method was used to determine concentration of total platinum in serum. 10 patients of digestive system neoplasm were divided into 2 groups according to different dose （85mg/m² or 130mg/m²）. After 2h administration by intravenous infusion, to determine the free- platinum and total- platinum concentration in serum at Oh, 0.5h, 1h, 2h, 4h, 8h, 16h, 24 and 48h, and drawing C-T curve, to calculate all pharmacokinetic parameters and blood-proteins bonding rate of two groups. The Kromasil C-18 column （250mmxxxxx4.6mm,5μm） was used. The mobile phase consisted of methanol-water （75:25）, the flow rate was 0.8ml/min, the detection wavelength was at 254nm, the sample size was 20μl and the column temperature was at the room temperature.Results:1. The L-OHP presented a good linear correlation between concentration and area of peak within a range of 9.432-94.32μg·ml^-1, r=0.9999 （n=7）. The average recovery was 100.30%, RSD=0.89%. When L-OHP combination with dexamethasone, in the condition of 25℃and 42℃, the content of L-OHP didn’t have marked change in 8 hours. When L-OHP combination with procaine at 25℃, the content of L-OHP didn’t have marked change in 2 hours. At 42℃the content of L-OHP obviously degraded. When L-OHP was mixed with lidocaine, white flocculent precipitate was appeared. The concentration of L-OHP in peritoneal cavity tluids decreased about 50% in 8h, and almost disappeared in 24h.2. The L-OHP presented a good linear correlation between concentration and area of peak within a range of 0.1-8ug/ml, Y=0.1101X-0.0045 （r=0.9991. n=7）. The relatively recovery of free- platinum was 91.83%, RSD= 9.60%,the relatively recovery of bounding-platinum was 91.79%, RSD=9.94%, lowest detectable limit was 0.03μg/ml. It showed high blood-proteins bonding rate in two groups, and increasing followed time delay, the low dosage group increased obviously more than high dosage group. Pharmacokinetic parameters after once administration in two groups showed thatα、V₁、AUC_0-t、K₁₀、MRT_0-t in free- platinum andα、β、t_1/2β、V₁、AUC_0-t、AUC_0-∞、K₂₁、MRT_0-t、MRT_0-∞ in total platinum had significant difference.Conclusion:1. The method in vivo and in vitro to determine L-OHP was simple, sensitive and accurate.2. In vitro study, mixed with dexamethasone at 42℃, L-OHP shows good stability, and mixed with procaine at 25℃, L-OHP shows good stability in 2 hours. L-OHP can’t mix with lidocaine. The dosage （130mg/m²） used in heated intra-operative intra-peritoneal therapy was safety, but the effectivity should be studied later.3. The high blood-proteins bounding rate of L-OHP in different dosages in digestive system neoplasm treatment demonstrated particularity of this kind of anti-cancer drugs in pharmacokinetic and mechanism of action.4. Partial pharmacokinetic parameters after once administration between high dosage and low dosage showed significant difference, pharmacokinetics progress of high dosage was beneficial to accomplish therapeutical effect.

Oxaliplatin: Investigation of Safety in Heated Intra-peritoneal Perfusion and Pharmacokinetic Study

Abstract

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