Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs.
OBJECTIVE
To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs.


METHODS
Dog and human liver microsomes and CYP3A4 were incubated with [(14)C]GLS4 for 15 min and then analyzed using a HPLC-dynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry.


RESULTS
The metabolic profile of [(14)C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively.


CONCLUSIONS
GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.
Centre for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Xin
X
Zhou
Zhi-wei
ZW
Gao
Jian
J
Meng
Xiao-yan
XY
Chen
Da-fang
DF
Zhong
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D013844:Thiazoles / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C588160:ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(2-thiazolyl)-1,4-dihydropyrimidine-5-carboxylate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D012293:Rifampin