Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans.
OBJECTIVE
To investigate the likelihood of artemisinin and thiabendazole causing pharmacokinetic interactions involving cytochrome P450 (CYP1A2) in humans given their potent inhibitory effects on the isoform in vitro.


METHODS
Ten healthy volunteers received caffeine (136.5 mg), and after a washout period of 48 h, the volunteers were given a caffeine tablet (136.5 mg) together with thiabendazole (500 mg). After an additional 14 days, the volunteers received caffeine together with artemisinin (500 mg). After each treatment, plasma was obtained up to 24 h post-dose. The plasma concentrations of the drugs were measured by HPLC with UV and MS detection.


RESULTS
Using the ratio of paraxanthine to caffeine after 4 h as an indicator of CYP1A2 activity, thiabendazole and artemisinin inhibited 92 and 66%, respectively, of the enzyme activity in vivo. In addition, the pharmacokinetics of caffeine were altered in the presence of the drugs; increases in AUC(0-24) of 1.6-fold (P < 0.01) and 1.3-fold of caffeine in the presence of thiabendazole and artemisinin respectively were measured. The use of in vitro data to predict the effects of thiabendazole on the formation of paraxanthine yielded good results and underestimated the effects of artemisinin when total plasma concentrations were used. Corrections for protein binding resulted in underestimation of inhibitory effects on CYP1A2.


CONCLUSIONS
Co-administration of thiabendazole or artemisinin with CYP1A2 substrates could result in clinically significant effects. Our results highlight the validity of in vitro data in predicting in vivo CYP inhibition. The formation of paraxanthine seems to be a better indicator of in vivo CYP1A2 activity than caffeine levels.
Bapiro
Tashinga E
TE
African Institute of Biomedical Science & Technology (AIBST), P.O. Box 2294, Harare, Zimbabwe.
Sayi
Jane
J
Hasler
Julia A
JA
Jande
Mary
M
Rimoy
Gerald
G
Masselle
Amos
A
Masimirembwa
Collen M
CM
D000328:Adult; D000962:Antimalarials / Q000494:pharmacology*; D000969:Antinematodal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D037621:Artemisinins / Q000494:pharmacology*; D002110:Caffeine / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D013806:Theophylline / Q000378:metabolism; D013827:Thiabendazole / Q000378:metabolism / Q000494:pharmacology*
D000962:Antimalarials; D000969:Antinematodal Agents; D037621:Artemisinins; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; D013827:Thiabendazole; C021183:1,7-dimethylxanthine