Pharmacokinetic profile of the anti-sickling hydroxyurea in wild-type and transgenic sickle cell mice

The pharmacokinetic profile of hydroxyurea (HU) was investigated by measuri ng the rate of drug disappearance from the plasma in wild-type and transgen ic (Tg) sickle cell mice. The absorption and elimination processes of HU ex hibited first-order kinetics after intraperitoneal administration of HU at 10, 50, 100 or 200 mg/kg body weight (BW). The dosage had a marked effect o n the pharmacokinetics of HU in the Tg sickle cell mice. Although the area under the plasma concentration curve (AUC) increased in direct proportion w ith the HU dose in the wild-type mice, the AUC increased to a much greater extent at higher doses in the Tg sickle cell mice. In the Tg sickle cell mi ce, there was a considerable increase in the mean residence time (MRT) and a significant reduction in the apparent clearance (CL/F) at HU dose greater than or equal to 100 mg/kg BW, when compared to the lower doses. At an HU dose of 200 mg/kg BW, the CL/F in the Tg sickle cell mice was reduced by ab out 50% of the value obtained at a dose of 10 mg/kg BW. This phenomenon was not noticeable in the wild-type mice. The MRT value in the wildtype mice a t all doses was relatively constant. The steady-state distribution volume o f HU in both the wild-type and Tg sickle cell mice was relatively constant at all doses of the drug. The AUG, CL/F, MRT, and terminal half-life values at any given HU dose showed significant differences between the wild-type and Tg sickle cell mice. Following intraperitoneal administration of HU at a dose of 10, 50, 100, or 200 mg/kg BW, the mean percentage of HU excreted in the urine of the wild-type and Tg sickle cell mice over 120 min was 84 /- 6.4% and 50 +/- 8.2%, respectively, indicating a significant difference in the amount of HU excreted in urine in the two kinds of mice. The results obtained in this study may be useful in establishing an optimal dose of HU in the treatment and management of patients with sickle cell disease and o ther hemoglobinopathies. Copyright (C) 2001 S. Karger AG, Basel.