Back to the Top
I have a question about the oral bioavailability and clearance. According to PK concept,
F=Fa*Fg*Fh, where Fa is the fraction of oral absorption, Fg is the fraction that escape intestinal
metabolism, Fh is the fraction that escape hepatic metabolism. Among of them, Fh=1-CL/Qh, where CL
is the hepatic clearance, and Qh is the hepatic blood flow. So based on this equation, if CL>=Qh,
then F will be approaching zero. But in reality, this will not always happen like this. I have met
some compounds that showed CL close or even higher than Qh, but F is still acceptable with the value
of around 30~40%. This F value was obtained from iv and po dosing routes with same dose level, so
non-linearity can be excluded. Besides that, renal clearance is also minimal based on the mass
balance study.
So why did this happen? Does this conflict with the PK theory?
It will be much appreciated that anyone can provide some suggestions and explanations.
Thanks,
Jian
Back to the Top
Hi Jian,
A couple of clarifications before I get to the main point. For your FH
estimation, the equation should read: FH=1-(CLH/QH), where CLH is the
hepatic clearance (not the total clearance) and QH is the hepatic blood
flow. Now in your statement "I have met some compounds that showed CL
close or even higher than Qh,...", if you refer to CLH, then the
question to you is how the liver can eliminate more drug than it
encounters? In other words, the maximum CL of any organ is the volume of
blood it receives and hence your next statement that you have seen drugs
with higher CL(H) than QH is incorrect. On the other hand, if by CL, you
mean total CL, there is no conflict with CL larger than QH and F around
30 to 40%: your drug is cleared possibly in the liver but also elsewhere
than the liver with the latter resulting in higher total CL than liver
blood flow, i.e., CLH is less than QH and hence the drug is bioavailable.
Toufigh
--
Toufigh Gordi, PhD
Back to the Top
My humble opinion to this issue is:
1. you need to change CL to CLb (blood total) before comparing with Qh
2. as Toufigh mentioned, CLb>Qh is normal. although you CLr is minimal but extra-hepatic CL can be
considered.
3. F=Fa*Fa*Fh is correct, but Fh=1-CLh/Qh is not always correct. Remember it is derived from simple
"steady-state" well-stirred model. Pay attention to this prerequisite. It is not always the case.
Especially, for high hepatic extraction compound, within a single dose, steady state can not be
always achieved. And if there is hepatic transporter involved, (for high hepatic-extracted compound,
I expect influx transporter involved,) it will also be much complicated with well-stirred condition
not matched.
Thanks
Gary
Back to the Top
Hi Toufigh,
Thanks for your response. Sorry for that I did not clarify it clearly. Yes, I know that
CLtot=CLH+CLR+CLother, where CLtot is obtained from dose divided by AUC under IV administration
route, and CLH is hepatic CL, CLR is renal CL, CLother is clearance happened in other tissues or
organs. As I mentioned, this compound showed un-obvious renal CL with few prototype excreted via
urine, so CLR can be neglected. For CLother, as I know, except the esterase metabolism which can
happen even in circulating system and bring a very high CLother sometimes (not for this compound),
if for oxidation type of metabolism, the major organ should be liver, although other tissues such as
kidney and lung, also can contribute to some extent, but should be far lower than in liver. So I
think the contribution of CLother is limited and can also be neglected. As for metabolism in the
enterocytes, I think this is also part of first pass metabolism, the metabolism happened here cannot
bring this kind of discrepancies between F and CL. Therefore, here, I assume CLtot is equal to CLH.
And that's why I confused about the data. Maybe someone can give me some examples that CLother
also can provide a large of contribution to drug elimination but not happened during first pass. So
far I don't meet any cases like this except those drugs bearing high renal CL and esterase-related
CL.
Thanks,
Jian
--
Hi Gary,
Many thanks for your input. As for your opinions:
1. you need to change CL to CLb (blood total) before comparing with Qh
Response: Yes, this indeed should be considered when comparing with Qh. But in this case, we have
tested B to P ratio, which is close to 1. So I did not mention it here.
2. as Toufigh mentioned, CLb>Qh is normal. although you CLr is minimal but extra-hepatic CL can be
considered.
Response: Please refer to my response to Toufigh in the last email.
3. F=Fa*Fa*Fh is correct, but Fh=1-CLh/Qh is not always correct. Remember it is derived from simple
"steady-state" well-stirred model. Pay attention to this prerequisite. It is not always the case.
Especially, for high hepatic extraction compound, within a single dose, steady state can not be
always achieved. And if there is hepatic transporter involved, (for high hepatic-extracted compound,
I expect influx transporter involved,) it will also be much complicated with well-stirred condition
not matched.
Response: Yes, I know your means that well-stirred model may not be suitable for every compounds
especially for those with high hepatic extraction and parallel tube model or dispersion model maybe
a better choice here. But here I mentioned is if based on the CL data, FH is obviously
underestimated. If using dispersion model and paralell tube model, FH will be underestimated more
seriously. About the CLH and FH relationship among these three models, you can refer to the
publication as following:
U. Fagerholm. Presentation of a modified dispersion model (MDM) for hepatic drug extraction and a
new methodology for the prediction of the rate-limiting step in hepatic metabolic clearance.
Xenobiotica, 2009; 39 (1): 58-71.
Same thing for the cases when influx transporter involved in hepatic metabolism, such as OATP1B1
substrate, I think the FH should be even lower but not higher than we expected.
Thanks,
Jian
Back to the Top
Hi Jian,
I think there is always the inconsistency between "ideal scenario" and "reality'.
The equation itself describes the ideal condition in well-stirred model. The model is true when you
have the ideal accurate data.
However, the experiments generating the data can be problematic, e.g. insufficient subjects, poor
trial design, unvalidated LC/MS method and inaccurate sampling times etc. The calculation of
accurate CLtot really depends on how the experiment was designed, implemented, and analyzed.
Similarly, the accuracy of F depends on the design of clinical trials and quality of data. e.g. Is
it cross-over design so that intra-individual variability can be minimized? How is the
inter-individual variability? Body weight, female/male, fasting/fed, disease condition, age etc.
everything can influence the final outcome.
Hope this helps!
Jie
Back to the Top
Jian,
It seems we are back to my first point. If you assume your CLH is equal
to CLT, you need to explain how CLH can be higher than QH. In other
words, you need to answer this question: How can the volume of blood
cleared by an organ over a time unit be larger than the volume that
passes through the organ during that time unit? In my mind, since the
answer to the question is "it can't", I believe the assumption of
CLH=CLT is incorrect in your case.
Toufigh
Back to the Top
Dear Toufigh,
It seems that we are talking about different things. Yes, I know that in well-stirred model, it is
not reasonable if CLH higher than QH. But the question I raised here was how to explain the
discrepancy between CL and F. At this case, if F is around 40%, which means FH will be at least
0.4, actually maybe even higher. Then CLH will be no more than 0.6*QH. And CLother will be no less
than 0.4*QH since CLR is close to zero. So what kind of metabolism or tissue can contribute to such
high CL? That's what I confuse right now.
By the way, about CLH cannot exceed with QH, I think this theory is only right in well-stirred
model. If transporter invovled in the drug uptake into hepatocyte and prolong the retention time of
drug metabolism in it, I don't think this theory is still correct.
Thanks,
Jian
Back to the Top
Hi Jian,
I think nonlinear PK can not be excluded, according to what you said. Non-linear pk process can
occur during first-pass metabolism, because drug concentration in liver during first pass is much
higher than that after iv, especially for high extraction ratio drug.
Mengyao
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@lists.ucdenver.edu with "Bioavailability and Clearance" as the subject |
Copyright 1995-2014 David W. A. Bourne (david@boomer.org)