Experimental approaches to studies on drug metabolism and drug interactions in man: interaction of acyclic nucleoside phosphonates with human liver cytochromes P450 and flavin-containing monooxygenase 3.
OBJECTIVE
To determine a possible influence of acyclic nucleoside phosphonates on FMO3 and CYP activity at molecular level in vitro.


METHODS
Inhibition of individual CYP and FMO3 activities in the reconstituted system and in artificial membranes (bactosomes) was studied.


RESULTS
Activity of FMO3 was inhibited by PMPA and bisPOC-PMPA even at low levels of these drugs (below 100 microM). In reconstituted system with CYP2C9, no inhibition of CYP2C9 activity was observed. On the other hand, experiments based on membrane coexpressed system showed a modest extent of inhibition (for PMEA, PMPA, bisPOM-PMEA and bisPOC-PMPA the level of inhibition was 77.8%; 74.1%; 64.2% and 68.6%, respectively at 400 microM).


CONCLUSIONS
PMPA and bisPOC-PMPA are able to inhibit FMO3 activity at relatively low levels (10-100 microM) indicating a relatively specific interaction. Activity of CYP2C9 was affected when using the membranes coexpressed with NADPHcytochrome P450 reductase. This is probably due to more natural conditions for maintaining the CYP activity in bacterial membranes. As the inhibitor concentration in the systemic circulation does not exceed 2 microM, the probability of a significant in vivo effect of adefovir, tenofovir and the respective prodrugs on the microsomal system of cytochromes P450 and FMO3 is relatively low.
Matal
Jaroslav
J
Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
Orság
Jirí
J
Nekvindová
Jana
J
Anzenbacherová
Eva
E
Veinlichová
Alena
A
Anzenbacher
Pavel
P
Zídek
Zdenek
Z
Holý
Antonín
A
D000225:Adenine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D001419:Bacteria / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I; D008954:Models, Biological; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism; D063065:Organophosphonates / Q000493:pharmacokinetics*; D010105:Oxygenases / Q000378:metabolism*; D012107:Research Design; D000068698:Tenofovir; D014169:Transformation, Bacterial
D063065:Organophosphonates; C053001:adefovir; D003577:Cytochrome P-450 Enzyme System; D000068698:Tenofovir; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D009251:NADPH-Ferrihemoprotein Reductase; D000225:Adenine; C106812:adefovir dipivoxil