Developmental toxicity of the HIV-protease inhibitor indinavir in rats.

Abstract

BACKGROUND:

Indinavir is an antiviral agent used for the treatment of HIV infection. We studied its developmental toxicity in rats.

METHODS:

Pregnant animals were treated orally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of gestation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a control group of 17 rats was treated with the vehicle accordingly. Developmental landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was examined by electron microscopy.

RESULTS:

Fetal examination on day 21 of pregnancy showed no treatment-related effects on number, weight, and viability of the fetuses; however, an increased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testis. The most striking finding was unilateral anophthalmia, observed in 7 pups (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. Electron microscopy of liver samples showed hepatocellular inclusions of lipids and myelin figure-like structures in maternal livers and infiltration with granulocytes in offspring livers.

CONCLUSIONS:

Further studies on reproductive toxicity, including combinations of three or more antiretroviral agents as used therapeutically, are needed to determine the hazards of such a treatment.

• Authors: K Riecke, T G Schulz, M Shakibaei, B Krause, I Chahoud, R Stahlmann
• Journal: Teratology (Teratology) Vol. 62 Issue 5 Pg. 291-300 (Nov 2000) ISSN: 0040-3709 [Print] United States
• PMID: 11029147 (Publication Type: Journal Article)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• HIV Protease Inhibitors
• Indinavir
• Cytochrome P-450 Enzyme System

Topics

• Abnormalities, Drug-Induced (enzymology, etiology)
• Animals
• Anophthalmos (chemically induced)
• Body Weight (drug effects)
• Cytochrome P-450 Enzyme System (metabolism)
• Dose-Response Relationship, Drug
• Embryonic and Fetal Development (drug effects)
• Female
• Fetus (drug effects, pathology)
• HIV Protease Inhibitors (toxicity)
• Indinavir (toxicity)
• Liver (drug effects, metabolism, ultrastructure)
• Male
• Microscopy, Electron
• Microsomes, Liver (drug effects, metabolism)
• Ossification, Heterotopic (chemically induced)
• Pregnancy
• Rats
• Rats, Wistar
• Ribs (abnormalities)
• Spine (abnormalities, pathology)