Lani
12-31-2008, 10:41 AM
Pharmacokinetics May Explain Differences in Cisplatin and Oxaliplatin Ototoxicity
(Eureka News Service)
More cisplatin enters the inner ear in an animal model than oxaliplatin. The difference may explain why cisplatin treatment in humans can lead to hearing problems while oxaliplatin rarely does.
The amount of cisplatin a patient can tolerate is often limited by hearing damage induced by the drug, referred to as ototoxicity. Oxaliplatin is not frequently associated with the problem, despite the fact that both drugs are platinum compounds.
To find out why the difference exists, Victoria Hellberg, M.D., at the Karolinska Institutet in Stockholm, and colleagues measured the amount of cisplatin and oxaliplatin that reached the cochlea in guinea pigs following intravenous dosing of each drug.
The total platinum concentration in the cochlea was more than five-fold higher with cisplatin than with oxaliplatin following intravenous injection. The perilymphatic drug concentration was also higher in the cisplatin-treated animals than in those exposed to oxaliplatin.
"The differences in cochlear kinetics and cellular uptake that we found in the hearing end organ are sufficient to explain the difference in ototoxicity between cisplatin and oxaliplatin," the authors conclude.
OPEN ACCESS: Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity
(Journal of the National Cancer Institute)
Background: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.
Methods: In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.
Results: In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.
Conclusion: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
(Eureka News Service)
More cisplatin enters the inner ear in an animal model than oxaliplatin. The difference may explain why cisplatin treatment in humans can lead to hearing problems while oxaliplatin rarely does.
The amount of cisplatin a patient can tolerate is often limited by hearing damage induced by the drug, referred to as ototoxicity. Oxaliplatin is not frequently associated with the problem, despite the fact that both drugs are platinum compounds.
To find out why the difference exists, Victoria Hellberg, M.D., at the Karolinska Institutet in Stockholm, and colleagues measured the amount of cisplatin and oxaliplatin that reached the cochlea in guinea pigs following intravenous dosing of each drug.
The total platinum concentration in the cochlea was more than five-fold higher with cisplatin than with oxaliplatin following intravenous injection. The perilymphatic drug concentration was also higher in the cisplatin-treated animals than in those exposed to oxaliplatin.
"The differences in cochlear kinetics and cellular uptake that we found in the hearing end organ are sufficient to explain the difference in ototoxicity between cisplatin and oxaliplatin," the authors conclude.
OPEN ACCESS: Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity
(Journal of the National Cancer Institute)
Background: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.
Methods: In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.
Results: In HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.
Conclusion: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.