Evidence for time-dependent interactions between ritonavir and lopinavir/ritonavir plasma levels following P-glycoprotein inhibition in Sprague-Dawley rats.
Biol Pharm Bull
; 34(1): 66-70, 2011.
Article
in En
| MEDLINE
| ID: mdl-21212519
ABSTRACT
The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1 ritonavir, 20 mg/kg/d (n=18), group 2 ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3 LPV/r, 80 and 20 mg/kg/d (n=17) and group 4 LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 µg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidinones
/
Verapamil
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Ritonavir
/
Anti-HIV Agents
Limits:
Animals
Language:
En
Journal:
Biol Pharm Bull
Journal subject:
BIOQUIMICA
/
FARMACOLOGIA
Year:
2011
Document type:
Article
Affiliation country:
South Africa