Last Word on Viewpoint: pH Buffer capacity and pharmacokinetics: two remaining questions

We thank the colleagues (8) who contributed highly constructive comments on our Viewpoint (6). Two questions remain: 1) a very significant point raised by Dr. Thornell (8), the buffering capacity and pH-regulation in airway-surface liquid; and 2) the arterial blood nicotine pharmacokinetics (PK) versus E-liquid pH.

1) The respiratory tract functionally consists of the conducting zone and respiratory zone, i.e., alveolar regions. Aerosol particle size distribution determines the deposition sites in the respiratory tract. Many studies have reported that e-cigarette droplets are within the respirable size range, and most of them deposit in the alveolar regions (4). In the conducting zone, the bronchial and bronchiolar surface is covered by mucus. Absorption is minimum. E-cigarette droplets deposited in this area would be diluted and pH buffered by the mucus. While the nicotine could still interact with nAChRs on the bronchial-bronchiolar epithelial cells, the effects would be limited compared with the alveolar regions. In contrast, the inner surface of alveoli is covered by a thin layer of water with surfactant; the interactions of nicotine with the nAChRs on the epithelial cells are more direct, and coupled with the huge surface area in the alveolar regions would play a major role in absorption. However, the pH value and, more significantly, pH buffer capacity of the alveolar region inner surface lining fluid (ALF) are unclear and are the focus of the following discussion.

CO₂ diffuses freely through the membranes between pulmonary capillary blood and ALF, where:

$${\text{CO}}_2+{\text{H}}_{\text{2}}\text{O}\leftrightarrow {\text{H}}_{\text{2}}{\text{CO}}_{\text{3}}\leftrightarrow {\text{HCO}}_3^{-}+{\text{H}}^{+}\leftrightarrow {\text{CO}}_3^{2-}+2{\text{H}}^{+}$$

This reaction quickly reaches equilibrium with the aid of carbonic anhydrase. We assume this is the major contributor to the pH and pH buffer capacity of the ALF. On average, end-tidal CO₂ is 5% at rest. Around 500 mL of inhaled fresh air every breath mixes with gas of reserved and residual volume of ~5,500 mL in an adult (male). Therefore there is breath by breath variation of CO₂ concentrations in the lungs. The solubility of CO₂ (q) = 0.1105 g/100 g of water in 35°C at a partial pressure of 1 atm CO₂ (760 mmHg) (6a). The partial pressure of CO₂ in alveoli (Pco₂) = 40 mmHg (0.052 atm) on average at rest. The concentration in ALF would be:

$$\left[{\text{CO}}_2\right]=0.052\times q=0.00575\text{ g}/100{\text{ g H}}_2\text{O}=0.0013\text{ M}$$

We can estimate the pH and pH buffer capacity with the apparent pK_a = 6.35; the resulting pH is 4.62.

Buffer capacity is a function of [H⁺]:

$$\beta =2.303\times \left(\frac{K_{\text{w}}}{[{\text{H}}^{+}]}+[{\text{H}}^{+}]+{\displaystyle \sum \frac{C_{\text{buf}}\times K_{\text{a}}\times [{\text{H}}^{+}]}{{(K_{\text{a}}+[{\text{H}}^{+}])}^2}}\right)$$

where C_buf is the total concentration of the carbonate species (1). The results are shown in Table 1.

Table 1.

Estimated pH buffer capacity of ALF

pKaapp	pH	β (M/pH unit)
6.35	4.62	0.000109
	7.40	0.000226

pKa_app indicates the apparent pKa. Note that for the carbonate system, pKa₁ = 6.35 and pKa₂ = 10.33 (6a). The difference is tiny by introducing pKa₂ in the buffer capacity calculation. In the range of physiological pH and lower, pKa₂ is negligible.

For comparison, the estimated β value of ALF at pH 4.62 is 50-fold lower than that of blood, which is 0.005 (1).

The above calculations are an approximation. There are Cl^–/${\text{HCO}}_3^{-}$ anion exchanger, H⁺-pump, and H⁺-channel in alveolar epithelial cells. How these mechanisms contribute to buffering and regulation of acid-base balance in ALF remains to be determined (3).

How the e-cigarette aerosol deposited on the alveolar region is diluted and buffered by the ALF requires more research.

In addition, direct measurement of the pH and buffer capacity in the ALF in breathing animals in vivo or in humans is technically very challenging due to the tiny size of alveoli, respiratory movement, and variabilities caused by CO₂ exchange. Determinations of these parameters have important physiological significance.

2) A relevant issue is the correlation between the arterial nicotine PK and the pH of E-liquid. The PK is a good description of inhaled e-cigarette aerosol absorption in the lungs. However, evidence of this kind is lacking. Investigators have reported either nicotine PK without E-liquid pH measurement (5) or E-liquid pH of a variety of E-cigarette brands (7) but not PK. Burch et al. (2) reported a positive correlation between the pH in inhaled aerosolized nicotine and nicotine peak concentration in blood that was cited in our Viewpoint (6).

Finally, we hope that our Viewpoint (6) and the Commentaries (8) will stimulate further research on alveolar pH buffer capacity and how pH of inhaled nicotine/e-cigarettes affects the lung response and nicotine absorption, as well as the effects on health.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

X.M.S. and T.C.F. conceived and designed research; X.M.S. performed experiments; X.M.S. analyzed data; X.M.S. and T.C.F. interpreted results of experiments; X.M.S. drafted manuscript; X.M.S. and T.C.F. edited and revised manuscript; X.M.S. and T.C.F. approved final version of manuscript.