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We did some pk studies in mice via bolus iv and got CL values that are ridiculously high, some as high as 95 L/Hr/kg. Can anyone venture an explanation?
Thanks
Tai Wei
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Hello Tai Wei,
Remember that the observed Cl (or CL) is the total body clearence, incl. lung, liver etc sites of degradation as well as others (active eleimination, plasma instability ..)
kind regards
Dirk --
Dr. Dirk Scharn
Senior Scientist, DMPK
Jerini AG
Invalidenstrasse 130
10115 Berlin, Germany
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Dear Tai,
in the CL estimation we consider the ratio between dose and exposure, i.e. the indirect effect of disappearance of compound from sampling compartment (usually bloodstream) shown as PK curve trend. This means that any process contributing to the compound disappearance from bloodstream is estimated as clearance, including any non-physiological disappearance processes.
Only as example, we can look to a compound poorly soluble in plasma or blood.
This compound, after IV bolus (rapid administration) can precipitate by forming macro aggregates, or can aggregate with plasma proteins or with blood cells, etc. Aggregates are usually trapped in lungs (trapping of macro-aggregates is one of physiological activities of lungs) and this can be the reason for rapid compound disappearance from circulation. This rapid disappearance is obviously estimated as high clearance in a PK analysis.
A possible sign of this behaviour is a very high volume of distribution of central compartment (i.e. very far from 50 mL/kg) possibly in disagreement with initial expectations.
Kind regards
Stefano Porzio
--
Dr. Stefano Porzio
Bioanalytics and Pharmacokinetics
Laboratorio Integrato di Metodologie Avanzate
Bioindustry Park del Canavese S.p.A. - Bi.P.Ca S.p.A.
Via Ribes, 5
10010 Colleretto Giacosa (TO) - ITALY
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I am guessing that your IV formulation consists of some kind of co-solvent. So when you inject the formulation, cosolvent gets diluted in blood and drug compound precipitates out thus giving artificially high CL values.
Neil
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Intravascular metabolism instead of, or in addition to, hepatic?
Paul
--
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
777 Highland Avenue
Madison WI 53705-2222
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If you used a vehicle with a substantial proportion of organics, it's likely
the rapid clearance is the result of rapid partitioning of the compound out
of the central compartment into tissues. I would guess that your calculated
Vss value is also very high.
Mike Shirley
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Try simple explanations first: 1. Maybe your compound (very) extensively binds to red blood cells and most of it ends up in a trash bin when you separate plasma. It is not very common, but it does happen. 2. Are you sure you do not have ion suppression? It often is as extensive as it is stealthy.
3. Is your drug stable in whole blood? One hour incubation will give you the answer. In fact, in a way you are quite fortunate that the clearance is so ridiculously high - it means that something is so out of whack that you should be able to find the cause fairly easily.
Andrew
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RED CELL ACCUMULATION, Capillary, glomerular ppt, what happened to BP?
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Yes, and an elimination profile with a hump somewhat early on is a hallmark
of precipitation in the lung followed by slow dissolution of precipitate in
the pulmonary capillary bed.
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The easiest explanation, that hasn't been mentioned so far, is that you are measuring in plasma and the blood to plasma ratio is very high.
In mice hepatic blood flow is ~5.2 L/hr/kg. If your blood to plasma ratio is 40, as for cyclosporine, you could easily get 95. It is not experimentally difficult to determine blood/plasma ratio, and I recommend that it is value companies should always determine for their NMEs to anticipate unusual PK.
Leslie Z. Benet, Ph.D.
Professor
Department of Bioengineering & Therapeutic Sciences Schools of Pharmacy & Medicine
University of California San Francisco
533 Parnassus Avenue, Room U-68
San Francisco, CA 94143-0912
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Hi Tai Wei,
What kind of C0 values do you get? Is the compound poorly absorbed?
Thanks
Anila
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