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I would like to ask"to share your thoughts and views and give some
suggestions/comments regarding the interpretation of results from the
A bit of background:
Malarone is a fixed dose combination of atovaquone (250 mg) and
proguanil (100mg), used as a prophylactic against P. falciparum
malaria. These days it is increasingly been prescribed to healthy
individuals travelling to malaria endemic countries as an alternative
Atovaquone (366.84)"is a highly lipophilic drug, extensively (99.9%)
bound to plasma proteins, low biaoavalibilty (23%) after a single oral
dose, doesn't undergo phase 1 metabolism, no information about the drug
undergoing phase 2 metabolism, undergoes extensive enterohepatic
recycling and mainly eliminated through biliary excretion (>95%
eliminated in faeces after administration of" 14C radioactive
atovaquone in humans, <0.6% in urine). Elimination half life is rather
long 70-84 hrs. In a study in humans, when administered concurrently
with zidovudine, has shown to increase the concentration of zidovudine
and decrease"Z-glucuronide concentrations possibly by inhibitiion of
glucuronidation (main metabolic pathway for zidovudine). Also has shown
to increase concentrations of both etoposide and etoposide catechol
when administerd in combination with etoposide.
In an attempt to study the effect of ketoconazole and rifampicin on the
pharmacokinetics of atovaquone, we administered Malarone alone, in
combination with ketoconazole and in combination with rifampicin in
three different"periods using open label, crossover design in 10
In period 1, Malarone"one tablet was administered and samples were
collected at regular intervals untill 336 h. In period 2 and 3
ketoconazole and rifampicin were administerd for 11 days and on 4th and
6th days respectively one tablet of malarone was administerd, and
sample scollected as in period 1.
We compared the single dose PK of atovaquone in three periods.
Ketoconazole increased the mean AUC0-inf of atovaquone by 1.76 fold as
compared to Malarone alone. Cmax was also increased 1.7 fold but there
was no change in t\0x03A9 of atovaquone between"the two"periods.
In 3rd period,"on coadministration with rifampicin AUC of atovaquone
was 0.8 fold as compared to Malarone alone. No change in Cmax but t\0x03A9
was also 0.8 fold as compared to the 1st period.
Ketoconazole,"has been shown to inhibit CYP3A4, transport proteins such
as P-gp"and OATP"and UDP-glucuronyl-transferase enzymes in vitro.
Rifampicin"has been shown to induce"P-450 enzymes e.g. CYP3A4," P-gp
andUDP)-glucuronyl-transferase enzymes "(UGT 1A1 and UGT2B7)" and
inhibit MRP2"in humans."
Can we suggest an involvement of transport proteins, such as P-gp, MRP2
and/or OATP (uptake protein)? Is it a possibilty that atovaquone
undergoes glucuronidation by UGTs?
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