The effects of induced diabetes and cutaneous Leishmania infection on the pharmacokinetics of antimony in hamsters

Abstract

Patients with certain diseases appear to be at greater risk of developing adverse drug interactions, either because of the disease state itself or the drugs used to treat it. The effects of streptozotocin-induced diabetes and/or cutaneous Leishmania major infection on the pharmacokinetics of antimony (Sb^V) have now been investigated, in hamsters treated with sodium stibogluconate (Pentostam). The animals were randomly divided into five groups, each of 20 hamsters, known as D (for diabetes without leishmaniasis), DL (diabetes induced prior to the leishmaniasis), L (leishmaniasis without diabetes), LD (diabetes induced after leishmanial infection) and C (the control group, of animals with neither diabetes nor leishmaniasis). After its diabetes and/or leishmaniasis (if any) was established, each animal was given an intramuscular dose of sodium stibogluconate (80 mg/kg) each day for 3 weeks. Blood samples were collected after the first or last doses, to allow the pharmacokinetic parameters of Sb^V after single and multiple dosing to be compared.

Although the between-dose interval (24 h) was more than 10 times longer than the terminal elimination rate constant (t _½) at steady state, there was a significant increase in the mean peak Sb^V concentration (C _max), as the result of multiple dosing, in all five groups (P<0.001 for each). The hamsters with diabetes showed the least accumulation of Sb^V in their blood, whether or not they were infected with L. major. In the non-diabetic animals of groups L and C, the apparent total clearance of Sb^V (CL/F) was decreased by multiple dosing, being, respectively, 34.5% and 23.0% lower after the 21st dose than after the first. An increase in urine volume was the reason for the significant increase in CL/F in group D (P<0.001), and this offset the decrease in CL/F seen in the L group, resulting in no change in CL/F in the animals of the DL group.

Three weeks of antileishmanial treatment produced no significant reductions in the leishmanial lesions on the parasite-inoculated foot-pads of the hamsters in the L or DL groups but such reductions were detected in the animals of the LD group (P<0.001).

In conclusion, it appears that the administration of Sb^V over a few weeks may cause renal toxicity and, in clinical use, should therefore be accompanied by the regular monitoring of renal function. A cautious increase in Sb^V dosing may be necessary for the effective treatment of L. major (and perhaps other species of Leishmania) in diabetic patients.