Pharmacokinetics and Pharmacodynamics of Cannabinoids
Clin Pharmacokinet 2003; 42 (4): 327-360
THC is detectable in plasma only seconds after the first puff of a cannabis cigarette with peak plasma concentrations being measured 3–10 minutes after onset of smoking (figure 5).[35-40] Systemic bioavailability generally ranges between about 10 and 35%, and regular users are more efficient (table III). Bioavailability varies according to depth of inhalation, puff duration and breathhold. A systemic bioavailability of 23 ± 16% and 27 ± 10% for heavy users versus 10 ± 7% and 14 ± 1% for occasional users of the drug was reported. In a study with a smoking machine, patterns of cannabis smoking were simulated with regard to puff duration and volume, resulting in 16 to 19% of THC in the mainstream smoke. If the whole cigarette was smoked in one puff the percentage of THC in the mainstream increased to 69%. About 30% is assumed to be destroyed by pyrolysis. With smoking, additional THC is lost in the butt, in sidestream smoke, and by incomplete absorption in the lungs. Smoking a pipe that produces little sidestream smoke may also result in high effectiveness, with 45% of THC transferred via the mainstream smoke in one smoker tested.
3.1.2 Oral Administration
With oral use, absorption is slow and erratic, resulting in maximal plasma concentrations usually after 60–120 minutes (figure 6).[31,39,44] In several studies, maximal plasma concentrations were observed as late as 4 hours and even 6 hours in some cases.[39,41,46] Several subjects showed more than one plasma peak.[37,39,41] Delta-9-THC is expected to be degraded by the acid of the stomach and in the gut. At low pH, isomerisation to ?8-THC and protonation of the oxygen in the pyran ring may occur with cleavage to substituted CBDs. It has been suggested that a somewhat higher bioavailability is obtained in an oil formulation. However, absorption seems to be nearly complete in different vehicles. Ninetyfive percent of total radioactivity of radiolabelled THC was absorbed from the gastrointestinal tract in an oil vehicle and 90–95% if taken in a cherry syrup vehicle, but it is unclear from these data how much of this radioactivity belongs to unchanged THC and how much to breakdown products. An extensive first-pass liver metabolism further reduces the oral bioavailability of THC, i.e. much of the THC is initially metabolised in the liver before it reaches the sites of action. Ingestion of THC 20mg in a chocolate cookie and administration of dronabinol 10mg resulted in a very low systemic bioavailability of 6 ± 3% (range 4–12%) or 7 ± 3% (range 2–14%), respectively, with a high interindividual variation.
3.1.3 Ophthalmic Administration
A study in rabbits with THC in light mineral oil determined a variable systemic bioavailability of 6–40% with ophthalmic administration. Plasma concentrations peaked after 1 hour and remained high for several hours.
3.1.4 Rectal Administration
With rectal application, systemic bioavailability strongly differed depending on suppository formulations. Among formulations containing several polar esters of THC in various suppository bases, THC-hemisuccinate in Witepsol H15 showed the highest bioavailability in monkeys and was calcu- lated to be 13.5%. The rectal bioavailability of this formulation was calculated to be about as twice as high as oral bioavailability in a small clinical study.
3.1.5 Sublingual Administration
Clinical studies are under way using a liquid cannabis extract applied under the tongue. A phase I study in six healthy volunteers receiving up to 20mg of THC was reported to result in ‘relatively fast’ effects. In phase II studies, THC plasma concentrations of up to 14 µg/L were noted.
3.1.6 Dermal Administration In a study using the more stable ?8-THC isomer, the permeability coefficient of THC was significantly enhanced by water and by oleic acid in propylene glycol and ethanol, resulting in significant THC concentrations in the blood of rats. Studies designed to develop transdermal delivery of cannabinoids found a mean effective permeability coefficient for ?9-THC in propylene glycol of 6.3 × 10–6 cm/h.