Effects of lopinavir-ritonavir combined therapy during the rat pregnancy. Morphological and biochemical aspects.
OBJECTIVE
To evaluate the biochemical and morphological effects in rats subjected to three different dose associations of the protease inhibitors lopinavir and ritonavir administered throughout the entire period of pregnancy.


METHODS
The animals were treated throughout pregnancy with daily oral doses of lopinavir+ritonavir starting at the day one of pregnancy, and were divided into four groups: E1, 13.3+3.3 mg/kg; E2, 39.9+9.9 mg/kg; E3, 119.7+29.9 mg/kg and C, control (drug vehicle, propyleneglycol). The animals were then sacrificed and maternal blood and fetal and maternal organ samples were taken for morphological and biochemical analysis.


RESULTS
No major changes were identified in the group treated with the lowest dose as compared with the control. In the group E2, we found hepatocytes with signs of atrophy, eosinophilic cytoplasm, picnotic nuclei and vasodilatation. The proximal convoluted tubules of maternal kidneys showed eosinophilic areas and hyperchromatic nuclei, as well as signs of vasodilation. In the group treated with the highest dose (group E3), in the maternal kidneys and livers, the morphological changes were similar to those found in E2, although more prominent. Regarding the fetal organs, the single abnormality observed was some liver vasodilation in the group E3 (highest dose). The treatment with lopinavir+ritonavir caused discrete, yet significant, alterations of aspartate aminotransferase activity, blood urea nitrogen and creatinine plasma levels.


CONCLUSIONS
Our results showed that the administration of a combination of lopinavir plus ritonavir to pregnant rats can cause morphological as well as functional changes in maternal and fetal liver and kidneys and, in higher than therapeutic doses, might be toxic to those animals.
Cunha
A M
AM
Department of Obstetrics, Federal University of São Paulo, School of Medicine, S. Paulo, Brazil.
Hagemann
C C F
CC
Simões
R S
RS
Oliveira-Filho
R M
RM
Simões
M J
MJ
Soares
J M
JM
Maciel
G A R
GA
Oliveira
F H M
FH
Amed
A A
AA
Kulay
L
L
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D061466:Lopinavir; D011247:Pregnancy; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019438:Ritonavir