Hi, all friends
I am working on building a oral model with "Generic SimBiology PBPK model" and meet some problems about intestinal transit rate. Take duodenum as example, the transit rate is defined as " (kTransportSmallIntestine*organismLengthDuodenum/organismLengthSmallInstestine)*Duodenum.DrugDissolved". I think assuming duodenum transit time is equal to SmallIntestineTransittime*organismLengthDuodenum/organismLengthSmallInstestine, the transit rate constant is the inverse of that,which result in kTransportSmallIntestine*organismLengthSmallInstestine/organismLengthDuodenum, contradicting with the equation in model. Am I wrong?
Besides that, the kTransportSmallIntestine_is defined as _0.693/organismMeanResidenceSmallIntestine in model. Isn't the mean residence time determining the time at which about 63.2% of initial amount having passed through the compartment and inverse of mean residence time determining the transit rate? Why does organismMeanResidenceSmallIntestine correlate with 0.693 which is often seen in half-life associated expression?
Thanks for any comment.
6 Comments
Time Descending
Hi Wei Wang,
Sorry it took some time to get back to you. We needed some time to get to the bottom of this.
- I agree with you that implementation of the transit time is incorrect.
- The original paper (Sheila Peters, 2008) uses a Kt_i = 0.035, for each of the seven compartments, which corresponds to a transit time of 28.57 minutes for each compartment
- This is consistent with a Kt_total = 0.005 for the entire small intestine, which corresponds to a total transit time of 200 minutes (200/7 = 28.57), which is consistent with a publication I found
- The SimBiology implementation normalizes the transit time for each compartment by using the length of each compartment, length_segmenti.
- If we assume T_i = T_total*length_segmenti/length_total
- Then Kt_i = 1/T_i = 1/T_total * length_total/length_segmenti = Kt_total* length_total/length_segmenti
- And we can check that T_total = Sum (T_i) = 1/Kt_total * Sum(length_segmenti)/length_total = 1/Kt_total * 1
- Thus, Changing Kt_i = Kt_total*length_segment/length_total to Kt_i = Kt_total *length_total/length_segment solves the problem:
Regarding your second question, we are not sure where the factor 0.693 comes from. If you look at Sheila Peters’ paper, the small intestine transit rate Kt = 0.035 in humans, see table 1. As I explained above, this is consistent with a transit time of 200 minutes or 3 1/3 hr. In the Simbiology model
- The parameter Kt_total is called kTransportSmallIntestine
- With an initial assignment on kTransportSmallIntestine = 0.693/organismMeanResidenceSmallIntestine
- organismMeanResidenceSmallIntestine = 3.33 hours (200 minutes, see Yu and Amidon 1998).
- If we want to be consistent with the Peters’ paper, I think the factor 0.693 should change to 1 to result in kTransportSmallIntestine = 1 /organismMeanResidenceSmallIntestine
Sorry for the inconvenience and thanks for your message! We will update the FileExchange entry with these changes.
- Peters, S. A. (2008). Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis. Clinical pharmacokinetics, 47(4), 261-75.
- Yu, L.X. and Amidon, G.L. (1998). Characterization of small intestinal transit time distribution in humans. International Journal of Pharmaceutics, 171, 157-163.
Hi, Sietse Braakman ,
Thanks for your reply and it's really helpful. So where may I find the FileExchange entry in the future?
In the same place: link to entry We will change the version number from 1.2.0.0 to 1.2.1.0 once it is updated.
I have now updated the model on the FileExchange.
Thanks for your concern a lot.
Let me look into this and get back to you!
