Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant

Abstract

Radiation nephritis is the principle late toxicity seen after total body irradiation in barrier-maintained rats when hematologic toxicity is prevented by bone marrow transplantation. Renal dysfunction is observed for single doses as low as 7.5 Gy. Hepatic blood flow, as measured by indocyanine green clearance, is decreased after 8.5–9.5 Gy single-dose total body irradiation. Serum albumin levels are decreased after 9.5 Gy single-dose total body irradiation. Hypoalbuminemia is a symptom of hepatic damage, but can also be caused by renal damage or edema. No decrease in total serum protein is observed, indicating that proteinuria resulting from renal damage is not the cause of hypoalbuminemia. No edema and some dehydration are observed. These data indicate that hepatic damage as well as renal damage may be occurring after total body irradiation plus bone marrow transplantation. Animals given total body irradiation plus bone marrow transplantation show decreased tolerance to a wide variety of immunosuppressive and cytotoxic drugs, even when these drugs are given months after total body irradiation. Altered drug clearance after total body irradiation plus bone marrow transplantation is observed for cis-platinum, vincristine, and adriamycin. The increase in cis-platinum toxicity after total body irradiation plus bone marrow transplantation is caused by decreased renal drug clearance. The decrease in vincristine tolerance and the alterations in adriamycin and vincristine pharmacokinetics are caused by altered drug distribution after total body irradiation plus bone marrow transplantation. These results indicate that bone marrow transplant survivors may show altered clearance of, and decreased tolerance to, a wide variety of drugs that are used after bone marrow transplantation.