Prediction of milk plasma ratio for amphoteric substances

• Published in: Pharmacology research & perspectives Vol. 11; no. 1; pp. e01042 - n/a
• Main Authors: Jones, Sabrina, Al‐Doori, Fatimah, Fujiwara, Ryoichi
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2023; John Wiley and Sons Inc; Wiley
• Subjects: Acids; Animals; Breastfeeding & lactation; Drugs; Milk - chemistry; Pharmacokinetics; Pharmacology; Plasma; Surface-Active Agents
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.1042

[...]a research group reported a significant underestimation of M/P values for amphoteric small-molecule drugs. 2 As we revisited the original publication and carefully reviewed the recent report, 1,2 we learned that the poor prediction of M/P values for amphoteric drugs was due to the misemployment of pKa values. In this article, therefore, we will demonstrate the proper application of the prediction model for amphoteric small molecules. Since the concept of the prediction model is that a lipophilic, unionized, and unbound fraction of small molecules can distribute from maternal plasma (pH 7.4) to milk (pH 7.2) (Figure 1), the set of prediction equations uses log10P, log10D, pKa, and unbound fraction (fu). Since its basic pKa is closer to 7.2, which is the pH of human breast milk, its basic pKa should be used in the equation and codeine should be treated as a base. [...]in the mammary gland, there are transporter proteins potentially controlling the disposition of their substrates between plasma and milk. Since the prediction model (Equation 1–9) solely depends on the physicochemical properties of small molecules, naturally predicted M/P values would not be accurate for small molecules that are substrates for such transporters.