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The following message was posted to: PharmPK
Dear All,
We are doing a studywith oneof ourNCE at higher dose of 100 mg/Kg
dose. I am finding that systemic exposure is higher in case of oral
administration over IV administrationat 100 mg/Kg dose. As far as
formulation is concerned I am using the same formulation for both IV
and oral administration. Can any body suggest what can be the probable
reason(s) behind such behaviour.
Regards
Ravi Kanth Bhamidipati
Senior Pharmacologist
Dept.of Drug Metabolism and Pharmacokinetics
Discovery Research Division
Dr.Reddy's Laboratories Ltd.
Bollaram Road , Miyapur
Hyderabad - 500 050
Andhra Pradesh
India
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The following message was posted to: PharmPK
Dear Ravi,
a possible explanation might be saturation of plasma protein binding.
The
intravenous bolus dose might lead to high initial plasma concentrations
associated with increasing free fractions and rapid distribution into
other
tissues and enhanced elimination. Whereas the slower drug input after
oral
administration lead to lower Cmax with most drug bound to plasma
proteins
retaining the drug within the blood plasma, slowing down the
distribution
into drug eliminating tissues resulting in slower drug elimination.
This explanation would be supported by intravenous Cmax exceeding oral
Cmax.
If this is the case, you might want to check plasma protein binding in
the
corresponding concentrations range.
Best regards
Karin
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The following message was posted to: PharmPK
Ravi,
First-pass lung metabolism could be a possibility.
Sri
Srikumaran Melethil, PhD, JD
Attorney at Law
President/CEO, Law and Science Consulting
Professor Emeritus, Pharmaceutics
School of Pharmacy, University of Missouri-Kansas City
8428 Constance St.,
Lenexa, KS 66215
Phone: 913-492-8185 ; Fax: 913-888-1829
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The following message was posted to: PharmPK
Dear ravikanth,
what is the study design of the experiment, is it by sparse sampling?
If it is done by sparse sampling, the interindividual variability may
be the reason.
Dr. Jayasagar gundu
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The following message was posted to: PharmPK
Dear Ravi
Following problems may be there
1. Analytical techniques, get them audited internally by a
nonconcerned person.
2. Have you done tissue distribution studies following both the
routes of adminisration.
with best regards
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The following message was posted to: PharmPK
Dear Ravi,
Do you refer to bound or unbound concentration of the drug? If you look
a
total plasma concentration, a possible (straightforward) explanation is
purely statistical: Do you have good sampling time points to descibe the
AUC, especially for the iv route? How large was the variation of the
data
(can be quite high for oral doses as high as 100 mg/kg).
A biological explanation may be the induction of hepatic Cyps. As the
cmax
is higher after iv dosing, this may lead to the induction of hepatic
Cyps
and more rapid overall clearance of the drug, as compared with po
administration.
best regards,
Michael
Michael Gassen
Head of Pharmacology and Preclinical Development
4SC AG Fon: +49 89 700763-0
Am Klopferspitz 19a Fax: +49 89 700763-29
82152 Martinsried E-Mail: gassen.-at-.4sc.com
Germany Internet: www.4sc.com
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