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Hi,
I am studying drug-drug interactions in rats. I have 2 drugs : drug A;
CYP3A4 inducer and drug B; CYP3A4 inhibitor.
After the ORAL administration of a single dose of both of them (the
inhibitor first) drug B inhibit the metabolism of drug A (higher
T1/2,Tmax and Cmax and lower clearance compared with the
administration of the drug A alone)
My question is:can anybody tell me why the Tmax is higher??
Any help will be highly appreciated.
Regards,
Andy
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Hi Andy,
I can think of the following explanation: T max should be when the
rate of
absorption equals the rate of elimination; since the absorption kinetics
shouldn't be affected, and the elimination rate is lower, this equality
would be achieved later in time.
Hope this helps,
Best regards,
Vera
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Thank you Sue and Vera,
If the inhibitor of CYP3A4 is also inhibitor of Pgp. Would this
increses the Tmax of the other drug?
Regards,
Andy
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Hi Andy
That would affect the Cmax but not Tmax. Pgp acts as an efflux pump
and you can think of it only if your administered drug is substrate of
Pgp, what do you think?
Regards
Dr. Srinivas Rao
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Thank you Srinivas,
Yes, I think both of them are Pgp substrates. I am saying "I think"
because there is a controversy about them and there are different
opinions in the bibliogaphy.
Would Pgp affect the Tmax?
Regards,
Andy
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Hi Andy,
Increase in Tmax in the presence of CYP3A4 inhibitor has also been
observed when grapefruit juice was administered with itraconazle and
when cyclosporine was given with sirolimus. I may not have followed
your discussion entirely, but do you see a statistically significant
increase in tmax and is it clinically significant? Your compound may
have similar properties to cyclosporin, which is a CY3A4 (intestinal &
hepatic) and PgP inhibitor. I am not sure if this helps!
Refs
Therapeutic Drug Monitoring. 21(3):304, June 1999
Journal of Clinical Pharmacology, 2003; 43:1168-1176
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The following message was posted to: PharmPK
Dear Andy
If both of them are Pgp substrates then to large extent Cmax will be
affected and you are bound to get ambiguious Tmax. However, to confirm
that, you can plan a pilot study by coadministering the Pgp inhibitor.
Regards
Dr.Srinivas Rao
New Chemical Entity Research
Lupin Research Park
46A/47A, Village: Nande, Taluka: Mulshi
Pune-411 042, India
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