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Dear Forum members
I am getting a little confused regarding the clearance of theophylline and the caution for its use in patients with CHF. Theophylline is considered to be a low extraction ratio drug (ER=0.1), hence changes in the liver blood flow should not have a significant impact on the hepatic clearance unless the intrinsic activity of the hepatic enzyme changes. Then why does the clearance of theophylline decrease significantly (falls appox by 50%) when used in patients with CHF? I would appreciate if someone could explain or provide a reading reference.
I would appreciate a quick response.
Thanks
-- Manish
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The following message was posted to: PharmPK
Hi Manish Issar,
> I am getting a little confused regarding the clearance of theophylline and the caution for its use in patients with CHF. Theophylline is considered to be a low extraction ratio drug (ER=0.1), hence changes in the liver blood flow should not have a significant impact on the hepatic clearance unless the intrinsic activity of the hepatic enzyme changes. Then why does the clearance of theophylline decrease significantly (falls appox by 50%) when used in patients with CHF?
Most hepatic metabolism of drugs involves oxidation. This needs oxygen. Oxygen is cleared with a high extraction ratio so oxygen clearance is flow dependent. In CHF blood flow is low and so oxygen delivery to the liver is low and drug metabolism is impaired.
I don't have any references for this but it a plausible explanation for low extraction ratio drugs which exhibit lower clearance in CHF.
Nick
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The following message was posted to: PharmPK
Manish:
As you know there are clinical studies that demonstrate reduced theophylline clearance in patients with congestive heart failure. It is important to note the patients in these studies had advanced and decompensated heart failure. Although the data is not available I would assume that patients this sick had a significant amount of right heart failure including impaired oxygenation.
Certainly there would be decreased liver blood flow with left heart failure but it also appears that right heart failure is associated with decreased enzyme activity including CYP2D6. There is a suggestion that other CYP1A2 substrates have decreased clearance in patients with congestive heart failure. I would indeed expect that CYP1A2 activity is decreased in advanced congestive heart failure.
Sincerely,
Carol Collins
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The following message was posted to: PharmPK
Dear Nick,
As a follow up question. Would a drug with Extraction ratio of 0.1 have such a significant 50% reduction in clearance?
Aside the plausible explanation given, is there any equation that relates increase in unit of clearance with every unit increase in ER?
Thanks
Muyiwa
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The following message was posted to: PharmPK
Dear Muyiwa,
For any drug the general equation for hepatic clearance is QE (Q: hepatic blood flow, E= Extraction ratio). Regards,
Mahasen A. Radwan, Ph.D.
Professor of Clinical Pharmacy
Dept. of Clinical Pharmacy
College of Pharmacy
King Saud University
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Muyiwa,
> As a follow up question. Would a drug with Extraction ratio of 0.1 have such a
> significant 50% reduction in clearance?
Any drug, no matter what its ER, if it is dependent on delivery of oxygen (or other co-factors that the liver extract highly), would be expected to have a decrease in hepatic clearance in CHF. The key idea is that if the co-factor has a high ER it's delivery becomes the rate limiting factor for metabolism of the drug. How much drug clearance is reduced depends on severity of CHF but theophylline gives you a typical value.
> Aside the plausible explanation given, is there any equation that relates
> increase in unit of clearance with every unit increase in ER?
Organ Blood Clearance = OBF * ER
ER = OBF*CLi/(OBF+CLi)
CLi=CLiSTD * Fcofactor
OBF=Organ Blood flow, CLiSTD=Intrinsic clearance when Fcofactor=1 ('normal' co-factor delivery)
Fcofactor reflects the relative delivery of cofactor needed for the drug intrinsic clearance process.
Delivery of co-factor might be assumed to be proportional to co-factor clearance. If the co-factor itself has a high ER then its clearance and thus delivery for metabolism of drug will depend on OBF. Fcofactor could be 0.5 in CHF.
Nick
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The following message was posted to: PharmPK
Dear Manish
Hepatic clearance of low E drug is affected by the change in hepatic function and is independent of the change in blood flow (CL = CLint. x Fu) [CLint: Intrinsic Clearance, Fu: unbound fraction of drug]. CHF could produce hepatocellular damage due to hypoperfusion or congestion which will result in reduction in CLint. CHF could reduce hepatic function as well as hepatic flow, therefore, hepatic clearance of both high and low E can be affected.
I hope this will explain your results.
With my regards,
Mahasen A. Radwan, Ph.D.
Professor of Clinical Pharmacy
Dept. of Clinical Pharmacy
College of Pharmacy
King Saud University
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In this discussion, the (liver) well-stirred model was mentioned and I think it is useful to bear in mind its definition/assumptions described in:
Rowland M, Benet LZ and Graham GG (1973) Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Pharmacodynamics 1:123-136,
http://www.springerlink.com/content/h46j218q97445k0v/
Regards
Masoud
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