Contents
Teoreler Acknowledgements

Absorption

✶ Oral administration

Stomach is the first compartment of the gastrointestinal tract (GIT) in the PBPK model. The model simulates a fasted environment and the average resident time in the stomach was 0.5 h.

The small intestine has been divided into seven different compartments.1 Drug transition through the small intestine occurs depending on the various transit rates of stomach, duodenum, jejunum and ileum. The parameters for the transit rates across the GIT mimic the fasted state of a human. Absorption occurs simultaneously across the seven compartments of the small intestine. The administered oral drug is assumed to be in solution instantly for absorption. There is no reabsorption occurring from the colon.

PBPK absorption model

* - the absorption models would be improved in the future updates.

Intestinal metabolism and first pass metabolism have been included in the model before the drug reaches the systemic circulation. For this minimal absorption model, the fraction escaping the gut metabolism (Fg) and first pass (Fh) have been computed for a well-stirred model using the following equations: 2,3

Fg = Qg / (Qg + f ub × CLint,gut)

Fh = 1 - CLhep / Qh

where, Qg is the blood flow rate through the intestine, fub is the fraction unbound in blood, CLint,gut and CLhep are the intrinsic gut clearance and hepatic clearance respectively, Qhv is the total blood flow through the liver.

Read more about clearance parameters used in the PBPK models here.

✶ Parenteral administration

The dose for intravenous administration and infusion are given in the veinal compartment. Intramuscular and subcutaneous administration have a depot compartment for the administered dose and drug release occurs into the surrounding area around the depot. This area is considered as a percent of the muscle or adipose tissue and is represented as intramuscular or subcutaneous compartment in the PBPK model. This is a physiological representation of the drug released from the depot into the surrounding blood capillaries.


References

  1. Yu LX, Crison JR, Amidon GL. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. International Journal of Pharmaceutics. 1996;140(1):111-8. https://doi.org/10.1016/0378-5173(96)04592-9.
  2. Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metabolism and Disposition. 1987;15(5):710-7. https://dmd.aspetjournals.org/content/dmd/15/5/710.full.pdf.
  3. Ito K, Houston JB. Comparison of the Use of Liver Models for Predicting Drug Clearance Using in Vitro Kinetic Data from Hepatic Microsomes and Isolated Hepatocytes. Pharmaceutical Research. 2004;21(5):785-92. https://doi.org/10.1023/B:PHAM.0000026429.12114.7d.