Comparative pharmacokinetics of oxaliplatin (L‐OHP) and carboplatin (CBDCA) in mice with reference to circadian dosing time

Abstract

Carboplatin (CBDCA) and oxaliplatin (I‐OHP) are non‐nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg⁻¹) or I‐OHP (17 mg kg⁻¹). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset—HALO), intermediate (0 HALO) or high (8 HALO) toxicity.Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I‐OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I‐OHP had a high binding affinity for plasma proteins. Mean values of t_1/2α and mean residence time (MRT) of free Pt for I‐OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (V_di) of free Pt (10.5 mL) in mice. However, plasma clearance of I‐OHP was twice as high (1.06 mL min⁻¹) as that of CBDCA (0.58 mL min⁻¹). Free Pt AUCs were eight to ten times lower for I‐OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I‐OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C₀, t_1/2α, V_di) as well as mean residence time. The smallest V_di and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest V_di and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I‐OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities.The major pharmacokinetic differences between CBDCA and I‐OHP were related to both protein binding and RBC handling.