Drug Absorption and Bioavailability
Kate McCombe, Lara Wijayasiri, Paul Hatton, David Bogod in The Primary FRCA Structured Oral Examination Study Guide 2, 2017
where HA is the acid, A− is its conjugate base (i.e. the product that is now able to accept protons) and H+ its proton. The higher the value of Ka, the more readily the acid gives up its proton and dissociates. Ka can be expressed in its logarithmic form giving us the pKa.pKa is the negative log of the acid dissociation constant, and is defined as −log10 Ka.pKa is used because it yields more convenient units that are easier to use for practical purposes.The pKa of a drug is the pH at which it is exactly half dissociated, i.e. the drug is 50% ionised and 50% unionised.The larger the value of pKa, the less readily the acid dissociates to donate its H+ ion at a given pH, i.e. the weaker the acid. Conversely, the smaller the value of pKa, the more readily the acid donates its proton and the stronger the acid.Most drugs are either weak acids or weak bases. Unfortunately, you cannot tell from the pKa of a drug whether it is basic or acidic; this is a property of each drug you just have to learn.
Local Anesthetics and Additives
Bernard J. Dalens, Jean-Pierre Monnet, Yves Harmand in Pediatric Regional Anesthesia, 2019
Due to their amine portion, most local anesthetics are weak bases. In aqueous solutions, there is an equilibrium between the nonionized (free base) and ionized (cationic) forms.1,2 The degree of ionization depends upon the dissociation constant (Ka) of the conjugate acid, and upon the local hydrogen ion (H+) concentration. The ionization of a substance is usually evaluated by the pKa, which is the negative logarithm of the acid dissociation constant (Ka) and which represents the pH value at which the molecule is 50% ionized.
Acid–base disturbances
Martin Andrew Crook in Clinical Biochemistry & Metabolic Medicine, 2013
The Henderson–Hasselbalch equation expresses the relation between pH and a buffer pair – that is, a weak acid and its conjugate base. The equation is valid for any buffer pair, the pH being dependent on the ratio of the concentration of base to acid. Note that pKa is the negative logarithm of the acid dissociation constant (Ka), and, the larger the value of pKa, the smaller the extent of acid dissociation:
Recent advances in the targeting of systemically administered non-viral gene delivery systems
Published in Expert Opinion on Drug Delivery, 2019
Ikramy A. Khalil, Yusuke Sato, Hideyoshi Harashima
The apparent acid dissociation constant (pKa) is an important factor that affects the biodistribution and delivery efficiency of pH-sensitive cationic lipid-containing LNPs [48]. Jayaraman et al. demonstrated that an apparent pKa from 6.2 to 6.5 is optimal for the LNP-mediated hepatic delivery of siRNA through the screening of a series of pH-sensitive cationic lipids with different linker chemistries between hydrophobic scaffolds and amino moieties [49]. Although a lower pKa value promotes hepatocyte uptake through the endogenous ApoE-LDLR pathway due to its neutral properties in the blood stream, it causes an inefficient conversion to cationic properties in acidic endosomes, which results in poor endosomal escape. On the other hand, a higher pKa value means that cationic properties develop in the blood stream which causes enhanced clearance by the reticuloendothelial system and a decreased uptake by hepatocytes due to its cationic properties in the blood stream, which results in non-specific interactions with serum proteins followed by aggregation. Through screening, a DLin-MC3-DMA (MC3) with an apparent pKa of 6.44 was identified as the most potent lipid that showed a 50% effective dose (ED50) of 0.005 mg siRNA/kg in a mouse factor VII (FVII) model [49]. MC3 is currently used as the main component in Patisiran (ONPATTROTM), which is a first-ever RNAi drug [50].
Advances in the use of cell penetrating peptides for respiratory drug delivery
Published in Expert Opinion on Drug Delivery, 2020
Larissa Gomes dos Reis, Daniela Traini
Most of the cationic CPPs are characterized by the presence of arginine and lysine residues in their composition. The high equilibrium acid dissociation constant (pKa values) of the side chains of these amino acids of ~13.8 and 10.4, respectively, leads to a protonated state at pH 6.8–7.0 [20], making them cationic. The number of arginine and lysine residues in the peptide composition has been directly correlated to their internalization capabilities, with higher efficiency associated with arginine-containing peptides compared to lysine residues [18,21]. This greater efficiency can also be related to the higher pKa of arginine guanidinium group, that was shown to be still protonated when buried in a hydrophobic microenvironment like a protein or the lipid membrane [20]. This protonation effect could explain the differences between poly-arginine and poly-lysine peptides, and the better efficiency observed for arginine-containing CPPs in promoting endosomal escape [21].
Development of a lower-sodium oxybate formulation for the treatment of patients with narcolepsy and idiopathic hypersomnia
Published in Expert Opinion on Drug Discovery, 2022
Gunjan Junnarkar, Clark Allphin, Judi Profant, Teresa L. Steininger, Cuiping Chen, Katie Zomorodi, Roman Skowronski, Jed Black
After preclinical testing of several formulations, two initial mixed-cations candidates were identified and explored further: JZP-507 and LXB. JZP-507 contains 50% less sodium than SXB, whereas LXB contains 92% less sodium than SXB. A phase 1 healthy volunteer PK study demonstrated that JZP-507 was bioequivalent to SXB. In another phase 1 PK study in healthy volunteers, LXB was found to be bioequivalent for oxybate plasma AUC but non-bioequivalent for oxybate plasma Cmax (which was lower with LXB compared with SXB). The decision to move forward with LXB, the non-bioequivalent formulation, was based upon the greater reduction in sodium, which would better serve patients’ needs (Table 2; Figure 3). The total concentration of calcium, magnesium, potassium, and sodium oxybates in LXB oral solution is 0.5 g/mL, equivalent to 0.413 g/mL of oxybate. LXB has a solution pH range of 7.3–9.0 and an acid dissociation constant (pKa) of 4.47. Cation amounts of 34.3 mEq calcium, 15.0 mEq magnesium, 16.4 mEq potassium, and 5.7 mEq sodium are present in the volume of solution delivering 9 g of LXB.
Related Knowledge Centers
- Acid
- Chemical Equilibrium
- Chemical Reaction
- Chemistry
- Equilibrium Constant
- Acid Strength
- Solution
- Dissociation
- Acid–Base Reaction
- Conjugate