Morphological and biochemical appraisal of the liver and renal effects of indinavir on rat pregnancy.
Since indinavir is currently used in combination with other antiretroviral agents, there is a scarcity of studies in the literature on its single-drug perinatal safety. Thus, we decided to examine the gross maternal and fetal effects of indinavir administered alone during the entire period of rat pregnancy. Forty pregnant animals were assigned at random to four groups (C = control) treated with the drug vehicle (distilled water); the experimental groups were treated with indinavir as follows: E1 = 40 mg/kg; E2 = 120 mg/kg; E3 = 360 mg/kg from "zero" up to the 20th day of gestation. Drug or vehicle were administered daily by gavage. Each group consisted of ten animals. At term-pregnancy, the rats were deeply anesthetized and blood samples were collected for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), creatinine and urea determinations. Fragments of maternal and fetal livers and kidneys were taken and routinely processed for histopathological study. Serum ALT activity in the E2 group was significantly higher (p < 0.01) than that of the other groups. The concentration of creatinine in blood was lower in the E2 and E3 groups than in group E1 (p < 0.01), whereas blood urea in group E3 was significantly lower than in the other groups (p < 0.01). Morphological (light microscopy) studies revealed that no significant effects of the drug could be detected regarding either maternal or fetal organs of the E1 and E2 groups. However, the maternal hepatocytes in the E3 group showed heterochromatic nuclei. In addition, there was some fatty infiltration, congested sinusoids and portal dilation. Maternal kidneys in the E2 and E3 groups revealed vascular dilation around the convoluted tubules. Regarding the biochemical determinations, the alterations observed were mild, without biological relevance, thus indicating that the treatment with indinavir during the entire gestation was essentially devoid of hepatic or renal effects which could result in altered metabolic parameters. It is concluded that indinavir was well tolerated in therapeutic and even in 9-fold higher doses. Notwithstanding, discrete morphological alterations occurred in the maternal compartment, but with no functional expression that could indicate deleterious effects on mothers and/or fetuses.
Quintino
M P
MP
Federal University of São Paulo, School of Medicine, Brazil.
Simões
R S
RS
Oliveira
F H M
FH
Oliveira-Filho
R M
RM
Simões
M J
MJ
Nakamura
M U
MU
Kulay
L
L
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D022781:Hepatocytes / Q000187:drug effects*; D019469:Indinavir / Q000008:administration & dosage / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017154:Stromal Cells / Q000187:drug effects*
D017320:HIV Protease Inhibitors; D019469:Indinavir; D000410:Alanine Transaminase