Bioavailability and Pharmacokinetics of Natural Volatile Terpenes in Animals and Humans
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Review 495 Bioavailability and Pharmacokinetics of Natural Volatile Terpenes in Animals and Humans C. Kohlert1, I. van Rensen2, R. März3, G. Schindler4, E. U. Graefe1, M. Veit1,* 1 Zentralinstitut Arzneimittelforschung GmbH, Sinzig, Germany 2 Department of Pharmaceutical Biology, Julius-von-Sachs-Institute for Biosciences, University of Würzburg, Würzburg, Germany 3 Bionorica Arzneimittel GmbH, Neumarkt/Opf., Germany 4 Department of Medicine I, Department of Complementary Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany RevisionReceived: accepted: December April 27, 24, 2000; 1999; Received: Accepted: December April 27, 2000 24, 1999 Abstract: Herbal medicinal products containing natural vola- text of the safetyof herbal medicinal products containing nat- tiles are used in the treatment of gastrointestinal diseases, ural volatiles. However, pharmacokinetics of volatile natural pain, colds and bronchitis. Many pharmacological studies re- compounds have not yet been investigated satisfactorily. For port a wide variety of in vitro effects, with anti-inflammatory several monoterpenoid and phenylpropanoid compounds and antimicrobial activities investigated most frequently. In there is a large amount of experimental data, but crucially± comparison, relatively few studies on the bioavailability and especiallywith respect to humans ± pharmacokinetic data are pharmacokinetics have been carried out. Thus, the relevance of lacking. the in vitro activity to the therapeutic effects found in individual studies or documented in textbooks of phytotherapy is still not This article reviews the data currentlyavailable on the sys- established. Further studies with essential oils and their single temic fate of natural volatile terpenes and phenylpropanes. compounds providing supporting evidence of efficacy and Unfortunately, methodological details, particularly concern- demonstrating systemic availability are necessary. Such data ing validation of the analytical methods used have not been could also be important in the context of safety. published for most of the studies. Therefore the results of those studies discussed here have to be considered cautiously, Key words: Terpenes, volatiles, herbal medicinal products, bio- since the assays used might not match the requirements for availability, pharmacokinetics. analytical validation. Absorption and Systemic Availability Introduction Dermal absorption Essential oils are mixtures of lipophilic, liquid, volatile, and Preparations of eucalyptus oil or mountain pine oil containing often terpenoid compounds present in higher plants. More a- and b-pinene, camphor, 3-carene, and limonene have been than 3000 compounds have been described so far (1). The used in most studies investigating the dermal absorption of clinical efficacyof volatiles is particularlywell-established for essential oil compounds. These monoterpenoid compounds chronic pulmonaryobstruction and acute bronchitis. For are readilyabsorbed after dermal application due to their lipo- these indications clinical trials have been carried out with philic character. In order to avoid pulmonaryabsorption of products containing 1,8-cineole (2), (3), (4), standardised myr- evaporating compounds, an external air supplywas provided tol (1,8-cineole, a-pinene, limonene) (5) and thyme extract for subjects in all studies. The skin did not represent a barrier (6), (7). Further clinical studies have been carried out with to the diffusion of essential oil compounds (17), (18). Applica- peppermint oil for the treatment of irritable bowel syndrome tion byointment to humans (19) and bybath to mice (18) re- (8), (9), non-ulcer dyspepsia (10), and tension-type headache sulted in a fast increase of plasma levels of the respective (11). Numerous essential oils and their components have compounds. Maximum plasma levels were reached within shown antimicrobial or antimycotic activity in in vitro studies 10 min of application (Fig.1). It was shown that the extent of (12), (13), (14), (15), (16). absorption depended on the size of treated skin area (18), skin properties, concentrations of the administered com- Various other in vitro activities of volatile oils or compounds pounds and on time of exposure (17). However, the latter re- have been reported. However, the clinical relevance of these sults were obtained in a studyperformed with onlyone sub- activities depends on the systemic availability of these com- ject and thus allow onlylimited conclusions (For details see pounds in the respective target organs. Thus, investigation of Tables 1 and 2). absorption, distribution and metabolism is necessaryto link in vitro with in vivo data. Theymayalso be important in con- Absorption after oral administration Planta Med 66 (2000) 495 ±505 Onlya few studies have addressed the absorption of volatile Georg Thieme Verlag Stuttgart · New York compounds after ingestion. From three studies with radio-la- ISSN: 0032-0943 beled 14C-citral and [1-14C]-trans-anethole administered to 496 Planta Med 66 (2000) C. Kohlert et al. rats, the rate of absorption was estimated from the recovery (Fig. 3) (26). As phase-II metabolites, glucuronides or sulfates of 14C in faeces or urine, respectively(20), (21), (22). The au- were detected in rats, rabbits, and humans (26), (27). Un- thors found 91±95% of the original activityin faeces and changed compounds could be detected onlyin small amounts urine and determined seven metabolites byHPLC. in 24 h urine (27). In a pharmacokinetic studywith human volunteers, enteric Several studies investigated the metabolic fate of t-anethole coated capsules containing a defined mixture of limonene, in humans and rodents (28), (29), (30). Determination of uri- 1,8-cineole and a-pinene, were investigated (41). As capsules narymetabolites suggested that in humans 14C-trans-ane- were administered uncrushed and crushed (as a surrogate of thole was completelymetabolised byoxidative O-demethyla- a liquid application), some information on the absorption of tion and various oxidative alterations of the side chain (30). 1,8-cineole, which was the onlycompound detected in suffi- Metabolites were excreted both unconjugated and conjugated cient quantities in the plasma of all patients, can be extracted to either glycine or glucuronic acid (29). No unchanged t- from this study. Patients who took the compounds as a capsu- anethole was detected in urine. The pattern of metabolites in le showed rather similar AUC values of 1,8-cineole to those human urine differed onlyquantitativelyfrom that seen in ro- who took the crushed capsules. The difference of the AUC of dent urine. A dose-dependent variation in urinarymetabolites both administration modes was smaller than 7%. As expected, was evident for t-anethole in rodents as well as 14C-eugenol the Cmax of crushed capsules was more than 25% higher, and in rats (31). For t-anethole the formation of phase-I metabo- 14 tmax was 0.75 h compared to 2.5 h with uncrushed capsules. lites was dose-dependent (28), whereas C-eugenol showed These data suggest that the upper part of the gastrointestinal dose-dependent variations of conjugates. tract has no significant role with respect to the absorption of 1,8-cineole, but additional data would be helpful for a better Metabolites of menthol and peppermint oil were investigated understanding of absorption of ingested volatile compounds. in several human studies (32), (33), (34). After oral applica- Data derived from radio-labeled compounds as published in tion of L-(±)-menthol or peppermint oil, respectively, 35±50% (20) are not sufficient, as long as no information on the identi- of the original menthol content was excreted renallyas men- tyof the carrier after metabolization is provided. thol glucuronide. Onlyone studyconducted byBell et al. ex- amined the free fraction of menthol and the glucuronide (34). Pulmonary absorption No unchanged menthol and onlytraces of the sulphate conju- gate were detected. There was a significant interindividual The volatile monoterpenes are particularlysuitable for inhala- variation in the quantities excreted, which is likelyto be due tion as used in the treatment of respiratorytract infections. to differences in absorption and dietaryhabits (33). After ad- Following inhalation, the compounds maybe absorbed bythe ministration of peppermint oil to ileostomypatients elimina- lung, and systemic availability is possible. In particular, for a- tion of menthol glucuronide was less than after administra- pinene, camphor and menthol this absorption route has been tion to healthysubjects. This indicated that absorption of confirmed experimentally. The reported range was 54±76% of menthol mainlytook place in the small intestine (32). the dose supplied with inhaled air (Fig. 2) (23), (24), (25). However, estimation of the amount absorbed bycalculating Other components of peppermint oil like menthone or the difference between inhaled and exhaled air does not ac- menthyl acetate were not assayed in these studies. However, count for various uncertainties, (e.g., regarding mucosal drug these components could easilybe metabolised to menthol deposition and metabolism) and does not consider distribu- and excreted as menthol glucuronide as well. tion into other compartments. These concerns were support- ed bya studythat measured blood levels, since only4±6% of The metabolic fate of menthol was studied in detail in rats af- the amount assumed to be absorbed was actuallyfound in ter oral administration (35), (36). Oxidation patterns were the blood