Bioavailability is a subset of absorption. It is the percentage of an administered dose that reaches systemic circulation. Therefore, by definition, when a drug is administered intravenously, its bioavailability is 100% as 100% reaches blood circulation.
Generally speaking, a drug’s oral bioavailability is the percentage of the drug dosage that eventually reaches circulation and the therapeutic site of action. Often an orally administered drug is metabolized and eliminated by the system before actually reaching systemic blood circulation and therefore its bioavailability is essentially 0%.
If the administered drug reaches 70% of the target value then it is considered to be 70% bioavailable.
A few definitions are needed to go any deeper:
- Lipophilicity – the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents.
Hydrophilicity – the ability of a chemical compound to dissolve in water.
- cLogP – a calculated logarithmic ratio between a compound’s lipophilicity and hydrophilicity – often called the Octanol/Water partition ratio. A cLogP of 0 means the compound is equally soluble in octanol and water. A high cLogP mean highly lipophilic and vice versa.
- LogS – predicts the intrinsic solubility of a compound in water as the log10 of thye solubility in moles/liter. This can be converted to grams/ml.
There has been a lot of conjecture concerning the bioavailability of CBD and CBDA in the literature but few actual studies. Without actual data, pharmacologists tend to make estimations based upon the lipophilicity or cLogP of the compound.
Most researchers use the ‘Lipinski’s Rule of 5’ to define a good drug candidate where the cLogP of a compound intended for oral administration should be <4.5. A more lipophilic compound will have low aqueous solubility therefore compromising bioavailability.
The cLogP for CBD is 6.33 whereas the cLogP for CBDA is 6.68. Not a great difference although cLogP is logarithmic.
Because lipophilicity is actually pH dependent, other pharmacologists prefer to use cLogD instead of cLogP to describe lipophilicity. The “rule of 3 states” that drug candidates should have a cLogD between 1 and 3 to have good bioavailability (lipophilicity).
Here is where the real difference lies. CBD is not ionizable at biological pH especially in saliva, which tends to range between a pH of 6.7 and 7.3. The cLogD for oral preparations of CBD is similar to its cLogP at 6.32. CBDA on the other hand, at a pH of 7 has a log D of 2.8228, within the range of good lipophilicity and therefore bioavailability!
The oral bioavailability of a drug is largely controlled by dissolution rate and solubility. The intrinsic solubility of CBD, predicted by logS, is 0.0004 mg/ml at any pH below 11.5.
CBDA on the other hand has a different profile: according to logS, at pH=6.5 its solubility is 2.20mg/ml, at pH=7.4 it is 17.49 mg/ml and at a pH=8 it is 69.62 mg/ml! This helps to understand why CBDA has a significant bioavailability.
Unpublished data by Nahler-19.7.2017 (BioBloom) states that CBDA should have a “log fold greater bioavailability” than CBD. One study by Pellesi et al., (Eur J Clin Pharmacol. 2018 Nov;74(11): 1472-1436) found CBDA to be 18X more bioavailable than CBD.
In another study by Jones et al., published in the 24th Annual Symposium of the International Cannabinoid Research Society 2014, found “the systemic bioavailability of CBDA following a single intraperitoneal administration 10mg/kg of pure CBDA a bioavailability of 80% where pure CBDA dosed at 10mg/kg orally showed a 19% bioavailability.
By Rob Wohleb PhD