Abstract:
BACKGROUND AND PURPOSE:Cultured pre-adipocytes accumulate and metabolize zidovudine (ZDV), but its mode of accumulation into these cells is unclear. We investigated the mode of accumulation of [(3)H]-ZDV, and the impact of changes in external pH and modulators of drug transporters on its accumulation and metabolism. EXPERIMENTAL APPROACH:The initial rate and steady-state accumulation of [(3)H]-ZDV were measured in 3T3-F442A cells. P-glycoprotein (P-gp) expression was detected by Western blotting. External pH was varied, and modulators of intracellular pH and drug transporters were used to study the mode of accumulation of ZDV. Phosphorylated ZDV metabolites were detected by high-performance liquid chromatography. KEY RESULTS:Intracellular accumulation of ZDV was rapid, reaching equilibrium within 20 min; nigericin increased accumulation by 1.9-fold, but this did not alter the generation of ZDV mono-, di- and triphosphate. The accumulation and metabolism were pH dependent, being maximal at pH 7.4 and least at pH 5.1. Monensin, carbonyl cyanide p-trifluoromethoxy) phenyl hydrazone, brefeldin A, bafilomycin A1 and concanamycin A increased accumulation; 2-deoxyglucose, dipyridamole, thymidine and tetraphenylphosphonium inhibited accumulation. The accumulation was saturable; the derived K(d) and capacity of binding were 250 nmol per 10(6) cells and 265 nM respectively. 3T3-F442A cells express P-gp; inhibitors of P-gp (XR9576 and verapamil), P-gp/BCRP (GF120918), multidrug resistance protein (MRP) (MK571) and MRP/OATP (probenecid) increased the accumulation of ZDV. Saquinavir, ritonavir, amprenavir and lopinavir increased accumulation. CONCLUSIONS AND IMPLICATIONS:The accumulation of ZDV in 3T3-F442A cells was rapid, energy dependent, saturable and pH sensitive. Western blot analysis showed that 3T3-F442A cells express P-gp, and direct inhibition assays suggest that ZDV is a substrate of P-gp and MRP.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Janneh O,Owen A,Bray PG,Back DJ,Pirmohamed Mdoi
10.1111/j.1476-5381.2009.00552.xsubject
Has Abstractpub_date
2010-01-01 00:00:00pages
484-93issue
2eissn
0007-1188issn
1476-5381pii
BPH552journal_volume
159pub_type
杂志文章abstract::1. TRPM8 (CMR1) is a Ca(2+)-permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to ment...
journal_title:British journal of pharmacology
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doi:10.1038/sj.bjp.0705652
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journal_title:British journal of pharmacology
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abstract::1. Neurally-evoked output of newly synthesized [3H]-acetylcholine from the rat phrenic nerve was measured in the absence of cholinesterase inhibitors. 2. Noradrenaline and isoprenaline enhanced neurally-evoked transmitter output markedly. Moreover, immediately after the application of noradrenaline the basal tritium e...
journal_title:British journal of pharmacology
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abstract::1. Plasma, peripheral and thoracic lymph concentrations of penicillin V, phenethicillin, carbenicillin, ampicillin, cloxacillin, penicillin G, chloramphenicol and sulphadiazine were determined at various time intervals up to 6 h following intramuscular administration of 50 mg/kg to dogs.2. Peak plasma concentrations o...
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journal_title:British journal of pharmacology
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pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17168.x
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