Percutaneous permeation enhancement by terpenes: Mechanistic view

AAPS Journal

Volumn 10, Issue 1, 2008, Pages 120-132

  Sapra, Bharti ^a   Jain, Subheet ^a   Tiwary, A K ^a  

^a PUNJABI UNIVERSITY   (India)

Author keywords

DSC; FTIR; Percutaneous permeation enhancement; Terpene; Transdermal

Indexed keywords

1,3,3 TRIMETHYL 2 NORCAMPHANONE; CARVACROL; CARVONE; CINEOLE; DICLOFENAC; ETODOLAC; FLUOROURACIL; HALOPERIDOL; HYDROCORTISONE; INDOMETACIN; INSULIN; KETOPROFEN; LIMONENE; LIMONENE OXIDE; LINALOOL; MENTHOL; MENTHONE; NEROLIDOL; NICARDIPINE; NICORANDIL; PINENE; PULEGONE; TAMOXIFEN; TERPENE; TERPENE DERIVATIVE; TERPENOID; TERPINEOL; THYMOL; UNINDEXED DRUG; ZIDOVUDINE;

CORRELATION ANALYSIS; DRUG ABSORPTION; DRUG ACTIVITY; DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG PENETRATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; SKIN ABSORPTION; STRATUM CORNEUM;

ADMINISTRATION, CUTANEOUS; ANIMALS; CHEMISTRY, PHARMACEUTICAL; DRUG CARRIERS; DRUG SYNERGISM; HUMANS; SKIN ABSORPTION; TERPENES;

EID: 51249092129     PISSN: 15507416     EISSN: None     Source Type: Journal    
DOI: 10.1208/s12248-008-9012-0     Document Type: Review

References (111)

1. T. Kurihara-Bergstrom, and W. R. Good. Skin development and permeability. J. Control. Release 6:51-58 (1987).
2. J. Shokri, A. Nokhodchi A. Dashbolaghi, et al. The effect of surfactants on the skin penetration of diazepam. Int. J. Pharm. 228:99-107 (2001).
3. N. Kannikkannan, K. Kanimalla S. S. Lamba, et al. Structure activity relationship of chemical penetration enhancers in transdermal drug activity. Cur. Med. Chem. 7:603-608 (2003).
4. B. J. Aungst, N. J. Rogers, and E. Shefter. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int. J. Pharm. 3:225-234 (1986).
5. H. Okabe, E. Suzuki T. Saitoh, et al. Development of novel transdermal system containing d-limonene and ethanol as absorption enhancers. J. Control. Release 32:243-247 (1994).
6. U. T. Lashmar, J. Hadgraft, and N. Thomas. Topical application of penetration enhancers to the skin of nude mice; a histopathological study. J. Pharm. Pharmacol. 41:118-122 (1989).
7. H. Okamoto, M. Ohyabu M. Hashida, et al. Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties. J. Pharm. Pharmacol. 39:531-534 (1987).
8. R. A. Thakur, Y. Wang, and B. B. Michniak. Essential oils and terpenes. In E. W. Smith, and H. I. Maibach (eds.), Percutaneous Penetration Enhancers, CRC Press, Boca Raton, 2006, pp. 159-173.
9. A. C. Williams, and B. W. Barry. Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm. Res. 8:17-24 (1991).
10. FDA. Part 182 substances generally recognized as safe. http://www.cfsan.fda.gov/~Ird/fcf182.html. Acessed on Nov 30, 2006.
11. M. A. Yamane, A. C. Williams, and B. W. Barry. Effects of terpenes and oleic acid as skin penetration enhancers towards 5-fluorouracil as assessed with time; permeation, partitioning and differential scanning calorimetry. Int. J. Pharm. 116:237-251 (1995).
12. M. A. Yamane, A. C. Williams, and B. W. Barry. Terpene penetration enhancers in propylene glycol/water co-solvent systems: Effectiveness and mechanism of action. J. Pharm. Pharmacol. 47:978-989 (1995).
13. A. F. El-Kattan, C. S. Asbill N. Kim, et al. The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. Int. J. Pharm. 215:229-240 (2001).
14. P. F. C. Lim, X. Y. Liu L. Kang, et al. Limonene GPI/PG organogel as a vehicle in transdermal delivery of haloperidol. Int. J. Pharm. 311:157-164 (2006).
15. N. González, and H. Sumano. Design of two liquid ibuprofen-poloxamer-limonene or menthol preparations for dermal administration. Drug Deliv. 14:287-293 (2007).
16. T. Tas, Y. Ozkan, A. Okyar, and A. Savaser. In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers. Drug Deliv. 14:453-459 (2007).
17. H. K. Vaddi, P. C. Ho Y. W. Chan, et al. Oxide terpenes as human skin penetration enhancers of haloperidol from ethanol and propylene glycol and their modes o action on stratum corneum. Biol. Pharm. Bull. 26:220-228 (2003).
18. B. M. Magnusson, P. Runn K. Karlsson, et al. Terpenes and ethanol enhance the transdermal permeation of the tripeptide thyrotropin releasing hormone in human epidermis. Int. J. Pharm. 157:113-121 (1997).
19. S. T. K. Narishetty, and R. Panchagnula. Transdermal delivery of zidovudine: Effect of terpenes and their mechanism of action. J. Control. Release 95:367-379 (2004).
20. S. T. K. Narishetty, and R. Panchagnula. Effect of l-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J. Control. Release 102:59-70 (2005).
21. Y. S. R. Krishnaiah, V. Satyanarayana, and R. S. Karthikeyan. Penetration enhancing effect of menthol on the percutaneous flux of nicardipine hydrochloride through excised rat epidermis from hydroxypropyl cellulose gels. Pharm. Dev. Tech. 7:305-315 (2002).
22. T. T. Kararli, C. F. Kirchhoff, and S. C. Penzotti. Enhancement of transdermal transport of azidothymidine (AZT) with novel terpene and terpene like enhancers: In vivo-in vitro correlations. J. Control. Release 34:43-51 (1995).
23. Y. S. R. Krishnaiah, V. Satyanarayana, and P. Bhaskar. Enhanced percutaneous permeability of nicardipine hydrochloride by carvone across the rat abdominal skin. Drug Dev. Ind. Pharm. 29:191-202 (2003).
24. Y. S. R. Krishnaiah, P. Bhaskar, and V. Satyanarayana. Penetration enhancing effect of ethanol-water solvent system and ethanolic solution of carvone on transdermal permeability of nimodipine from HPMC gel across rat abdominal skin. Pharm. Dev. Tech. 1:63-74 (2004).
25. A. Nokhodchi, K. Sharabiani M. R. Rashidi, et al. The effect of terpene concentrations on the skin penetration of diclofenac sodium. Int. J. Pharm. 335:97-105 (2007).
26. H. K. Vaddi, P. C. Ho Y. W. Chan, et al. Terpenes in ethanol: Haloperidol permeation and partition through human skin and stratum corneum changes. J. Control. Release 81:121-133 (2002).
27. H. K. Vaddi, P. C. Ho, and S. Y. Chan. Terpenes in propylene glycol as skin-penetration enhancers: Permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. J. PharmSci. 91:639-1651 (2002).
28. B. F. Van Duzee. Thermal analysis of human stratum corneum. J. Invest. Dermatol. 65:404-408 (1975).
29. G. M. Golden, D. B. Guzek R. R. Harris, et al. Lipid thermotropic transitions in human stratum corneum. J. Invest. Dermatol. 86:255-259 (1986).
30. K. Zhao, and J. Singh. Mechanisms of percutaneous absorption of tamoxifen by terpenes: Eugenol, d-limonene and menthone. J. Control. Release 55:253-260 (1998).
31. O. Pillai, and R. Panchagnula. Transdermal iontophoresis of insulin V. Effect of terpenes. J. Control. Release 88:287-296 (2003).
32. K. Knutson, R. O. Potts D. B. Guzek, et al. Macro and molecular physical chemical considerations in understanding drug transport in the stratum corneum. J. Control. Release 2:67-87 (1985).
33. H. Tori, and M. Tasumi. Theoretical analyses of the amide I infrared bands of globular proteins. In H. H. Mantsch, and D. Chapman (eds.), Infrared Spectroscopy of Biomolecules, Wiley-Liss, New York, 1996, pp. 1-18.
34. B. Norman Grainger, and W. Max. Herbal Drugs and Phytopharmaceuticals, A Handbook for Practice on a Scientific Basis with Reference to German Commission E Monographs, 2nd edn, CRC Press, New York, 2001.
35. D. Monti, P. Chetoni S. Burgalassi, et al. Effect of different terpene containing essential oils on permeation of estradiol through hairless mouse skin. Int. J. Pharm. 237:209-214 (2002).
36. H. Okabe, K. Takayama T. Nagai, et al. Effect of d-limonene and related compounds on the percutaneous absorption of indomethacin. Drug Des. Deliv. 4:313-321 (1989).
37. K. Kikuchi, K. Takayama, and T. Nagai. Effect of d-limonene on the amounts of ethanol and indomethacin penetrated from aqueous gel ointment to rat skin. Chem. Pharm. Bull. 40:3108-3109 (1992).
38. H. Okabe, K. Takayama, and T. Nagai. Percutaneous absorption of ketoprofen from acrylic gels patches containing d-limonene and ethanol as absorption enhancers. Chem. Pharm. Bull. 40:1906-1910 (1992).
39. N. Ohara, K. Takayama Y. Machida, et al. Combined effect of d-limonene and temperature on the skin permeation of ketoprofen. Int. J. Pharm. 105:31-38 (1994).
40. Y. S. R. Krishnaiah, D. V. Chandrasekhar B. Rama, et al. In vivo evaluation of limonene based transdermal therapeutic system of nicorandil in healthy human volunteers. Skin Pharmacol. Physiol. 18:263-272 (2005).
41. M. Hori, S. Satoh H. I. Maibach, et al. Enhancement of propranolol hydrochloride and diazepam skin absorption in vitro: Effect of enhancer lipophilicity. J. Pharm. Sci. 80:32-35 (1991).
42. H. Moghimi, A. Williams, and B. Barry. A lamellar matrix model for stratum corneum intercellular lipids. V. Effects of terpene penetration enhancers on the structure and thermal behavior of the matrix. Int. J. Pharm. 146:41-54 (1997).
43. H. Okabe, Y. Obata K. Takayama, et al. Percutaneous absorption enhancing effect and skin irritation of monocyclic monoterpenes. Drug Des. Del. 6:229-238 (1990).
44. C. K. Lee, T. Uchida K. Kitagawa, et al. Effect of hydrophilic and lipophilic vehicles on skin permeation of tegafur, alclofenac and ibuprofen with or without permeation enhancers. Biol. Pharm. Bull. 16:1264-1269 (1993).
45. C. K. Lee, T. Uchida K. Kitagawa, et al. Skin permeability of various drugs with different lipophilicity. J. Pharm. Sci. 83: 562-565 (1994).
46. C. A. Phillips, and B. B. Michniak. Transdermal delivery of drugs with differing lipophilicities using azone analogs as dermal penetration enhancers. J. Pharm. Sci. 84:1427-1433 (1995).
47. J. Borrras-Blasco, A. Lopez M. Morant, et al. Influence of sodium lauryl sulfate on in vitro percutaneous absorption of compounds with different lipophilicity. Eur. J. Pharm. Sci. 5:15-22 (1997).
48. D. A. Godwin, and B. B. Michniak. Influence of drug lipophilicity on terpenes as transdermal penetration enhancers. Drug Dev. Ind. Pharm. 25: 905-915 (1999).
49. A. F. El-Kattan, C. S. Asbill N. Kim, et al. The effects of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems. Int. J. Pharm. 198:179-199 (2000).
50. K. C. Sung, J. Fang, and H. O. Yoa-Pu. Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis. J. Control. Release 67:1-8 (2000).
51. C. M. Heard, D. Kung, and C. P. Thomas. Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the 'pull' effect. Int. J. Pharm. 321:167-170 (2006).
52. J. L. V. Anjos, D. S. Neto, and A. Alonso. Effects of ethanol/l-menthol on the dynamics and partitioning of spin-labeled lipids in the stratum corneum. Eur. J. Pharm. Biopharm. 67:406-412 (2007).
53. Y. Kaplun-Frischoff, and E. Touitou. Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids. Eur. J. Pharm. Sci. 86:1394-1399 (1997).
54. J. R. Kunta, V. R. Goskonda, H. O. Brotherton, M. A. Khan, and I. K. Reddy. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J. Pharm. Sci. 86:1369-1373 (1997).
55. S. Kitagawa, H. Li, and S. Sato. Skin permeation of parabens in excised guinea pig dorsal skin, its modification by penetration enhancers and their relationship with n-octanol/water partition coefficients. Chem. Pharm. Bull. 45:1354-1357 (1997).
56. D. Kobayashi, T. Matsuzawa K. Sugibayashi, et al. Analysis of the combined effect of 1-menthol and ethanol as skin permeation enhancers based on a two-layer skin model. Pharm. Res. 11:96-103 (1994).
57. Y. Maitani, K. Shimada, and T. Nagai. L-Menthol, oleic acid and lauricidin in absorption enhancement of free and sodium salt of diclofenac using ethanol treated silicone membrane as model for skin. Chem. Pharm. Bull. 44:403-408 (1996).
58. J. S. Chang, Y. H. Tsai P. C. Wu, et al. Effects of ethanol/l-menthol on the dynamics and partitioning of spin-labeled lipids in the stratum corneum. Eur. J. Pharm. Biopharm. 67:406-412 (2007).
59. J. L. V. Anjos, D. S. Neto, and A. Alonso. Effects of 1,8-cineole on the dynamics of lipids and proteins of stratum corneum. Int. J. Pharm. 345:81-87 (2007).
60. R. Prasad, V. Koul, S. Anand, and R. K. Khar. Effect of DC/mDC iontophoresis and terpenes on transdermal permeation of methotrexate: In vitro study. Int. J. Pharm. 333:70-78 (2007).
61. J. Negishi, K. Takayama Y. Higashiyama, et al. Promoting effect of O-alkylmenthol and O-acylmenthol derivatives on the percutaneous absorption of ketoprofen in rats. STP Pharma. Sci. 5: 156-164 (1995).
62. Y. Nakamura, K. Takayama K. Higashiyama, et al. Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen. Int. J. Pharm. 145:29-36 (1996).
63. Y. Obata, C. J. Li M. Fujikawa, et al. Evaluation of structure activity relationship of synthesized cyclohexanol derivatives on percutaneous absorption of ketoprofen using artificial neural network. Int. J. Pharm. 212:223-231 (2001).
64. Y. Obata, Y. Maruyama, and K. Takayama. The mode of promoting activity of O-ethylmenthol as a transdermal absorption enhancer. Pharm. Res. 23:392-400 (2006).
65. P. Cornwell, and B. W. Barry. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil. J. Pharm. Pharmacol. 46:261-269 (1991).
66. A. Arellano, S. Santoyo C. Martin, et al. Enhancing effect of terpenes on the in vitro percutaneous absorption of diclofenac sodium. Int. J. Pharm. 130:141-145 (1996).
67. P. Cornwell, B. W. Barry C. P. Stoddart, et al. Wide angle X-ray diffraction of human stratum corneum: Effects of hydration and terpene enhancer treatment. J. Pharm. Pharmacol. 46:938-950 (1994).
68. G. L. Xiong, D. Quan, and H. I. Maibach. Effects of penetration enhancers on in vitro percutaneous absorption of low molecular weight heparin through human skin. J. Control. Release 42:289-296 (1996).
69. R. Kadir, and B. W. Barry. a-Bisabolol, a possible safe penetration enhancer for dermal and transdermal therapeutics. Int. J. Pharm. 70:87-94 (1991).
70. F. Yamashita, and M. Hashida. Mechanistic and empirical modeling of skin permeation of drugs. Adv. Drug. Deliv. Rev. 55:1185-1199 (2003).
71. G. L. Flynn. Physicochemical determinants of skin absorption. In T. Gerrity, and C. Henry (eds.), Principles of Route-to-Route Extrapolation for Risk Assessment, Elsevier, New York, 1990, pp. 93-127.
72. N. E. Tayar, R. S. Tsai B. Testa, et al. Percutaneous penetration of drugs: A quantitative structure-permeability relationship study. J. Pharm. Sci. 80:744-749 (1991).
73. R. O. Potts, and R. H. Guy. Predicting skin permeability. Pharm. Res. 9:663-669 (1992).
74. R. O. Potts, and R. H. Guy. A predictive algorithm for skin permeability: The effects of molecular size and hydrogen bond activity. Pharm. Res. 12:1628-1633 (1995).
75. E. J. Lien, and H. Gao. QSAR analysis of skin permeability of various drugs in man as compared to in vivo and in vitro studies in rodents. Pharm. Res. 12:583-587 (1995).
76. M. T. Cronin, J. C. Dearden G. P. Moss, et al. Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur. J. Pharm. Sci. 7:325-330 (1999).
77. G. P. Moss, J. C. Dearden H. Patel, et al. Quantitative structure permeability relationships (QSPRs) for percutaneous absorption. Toxicol. In Vitro 16: 299-317 (2002).
78. S. Geinoz, S. Rey G. Boss, et al. Quantitative structure-permeation relationships for solute transport across silicone membranes. Pharm. Res. 19:1622-629 (2002).
79. S. Fujiwara, F. Yamashita, and M. Hashida. QSAR analysis of interstudy variable skin permeability based on the "latent membrane permeability" concept. J. Pharm. Sci. 92:1939-1946 (2003).
80. A. R. Katritzky, D. A. Dobchev D. C. Fara, et al. Skin permeation rate as a function of chemical structure. J. Med. Chem. 49:3305-3314 (2006).
81. I. T. Degim. New tools and approaches for predicting skin permeability. Drug Discov. Today 11:517-523 (2006).
82. D. Neumann, O. Kohlbacher C. Merkwirth, et al. A fully computational model for predicting percutaneous drug absorption. J. Chem. Inf. Model. 46:424-429 (2006).
83. T. Ghafourian, P. Zandasrar H. Hamishekar, et al. The effect of penetration enhancers on drug delivery through skin: A QSAR study. J. Control. Release 99:113-125 (2004).
84. S. Geinoz, R. H. Guy B. Testa, et al. Quantitative structure-permeation relationships (QSPeRs) to predict skin permeation: A critical evaluation. Pharm. Res. 21:83-92 (2004).
85. L. Kang, C. W. Yap P. F. C. Lim, et al. Formulation development of transdermal dosage forms: Quantitative structure-activity relationship model for predicting activities of terpenes that enhance drug penetration through human skin. J. Control. Release 120: 211-219 (2007).
86. A. C. Williams, and B. W. Barry. Penetration enhancers. Adv. Drug Del. Dev. 56: 603-618(2004).
87. K. Cal. How does the type of vehicle influence the in vitro skin absorption and elimination kinetics of terpenes? Arch. Dermatol. Res. 297:311-315 (2006).
88. J. Y. Fang, T. H. Tsai, Y. Y. Lin, W. W. Wong, M. N. Wang, and J. F. Huang. Transdermal delivery of tea catechins and theophylline enhanced by terpenes: A mechanistic study. Biol. Pharm. Bull. 30:343-349 (2007).
89. Y. Krishnaiah, S. Al-Saidan, D. Chandrasekhar, and V. Satyanarayana. Controlled in vivo release of nicorandil from a carvone-based transdermal therapeutic system in human volunteers. Drug Del. 13:69-77 (2006).
90. Y. S. R. Krishnaiah, V. Satyanarayana, and P. Bhaskar. Influence of limonene on the bioavailability of nicardipine hydrochloride from membrane-moderated transdermal therapeutic systems in human volunteers. Int. J. Pharm. 247:91-102 (2002).
91. Y. S. Krishnaiah, V. Satyanarayana, and R. S. Karthikeyan. Penetration enhancing effect of menthol on the percutaneous flux of nicardipine hydrochloride through excised rat epidermis from hydroxypropyl cellulose gels. Pharm. Dev. Technol. 7:305-315 (2002).
92. P. Ventura, M. Schiavi, and S. Serafini. The metabolism of trans-sobrerol in the rat. Xenobiotica 13:139-146 (1983).
93. P. Ventura, R. Pellegata, M. Schiavi, and S. Serafini. Biotransformation of trans-sobrerol. III. Metabolites of 8-hydroxycarvonacetone in the rat. Xenobiotica 16:317-323 (1986).
94. J. J. Diliberto, P. Srinivas O. Overstreet, et al. Metabolism of citral, an R,â-unsaturated aldehyde, in male F344 rats. Drug Metab. Dispos. 18:866-875 (1990).
95. S. A. Kouzi, J. D. McChesney, and L. A. Walker. Identification of four bilinary metabolites of the diterpene sclareol in the laboratory rat. Xenobiotica 23:621-632 (1993).
96. Y. Asakawa, T. Ishida M. Toyota, et al. Terpenoid biotransformation in mammals IV. Biotransformation of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid in rabbits. Xenobiotica 16:753-767 (1986).
97. T. Ishida, M. Toyota, and Y. Asakawa. Terpenoid biotransformation in mammals. V. Metabolism of (+)-citronellal, (+/-)-7-hydroxycitronellal, citral, (-)-perillaldehyde, (-)-myrtenal, cuminaldehyde, thujone, and (+/-)-carvone in rabbits. Xenobiotica 19: 843-855 (1989).
98. K. A. Eriksson, and J. O. Levin. Identification of cis- and trans-verbenol in human urine after occupational exposure to terpenes. Int. Arch. Occup. Environ. Health 62:379-383 (1990).
99. C. Köppel, J. Tenczer U. Tönnesmann, et al. Acute poisoning with pine oils metabolism of monoterpenes. Arch. Toxicol. 49:73-78 (1981).
100. W. Engel. In vivo studies on the metabolism of the monoterpenes S-(+)- and R-(-)-carvone in humans using the metabolism of ingestion-correlated amounts (MICA) approach. J. Agric. Food Chem. 49:4069-4075 (2001).
101. B. Moorthy, P. Madyashtha, and K. M. Madyastha. Metabolism of a monoterpene ketone, R-(+)-pulegonesa hepatotoxin in rat. Xenobiotica 19:217-224 (1989).
102. K. M. Madyastha, and N. W. Gaikwad. Metabolic fate of S-(-)-pulegone in rat. Xenobiotica 28: 723-734 (1998).
103. K. M. Madyastha, and C. Paul Raj. Studies on the metabolism of a monoterpene ketone, R-(+)-pulegonesa hepatotoxin in rat: Isolation and characterization of new metabolites. Xenobiotica 23:509-518 (1993).
104. P. Madyastha, B. Moorthy C. S. Vaidyanathan, et al. In vivo and in vitro destruction of rat liver cytochrome P-450 by a monoterpene ketone, pulegone. Biochem. Biophys. Res. Commun. 128:921-927 (1985).
105. L. J. Chen, E. H. Lebetkin, and L. T. Burka. Metabolism of (R)-(+)- pulegone in F344 rats. Drug Metab. Dispos. 29:1567-1577 (2001).
106. K. M. Madyastha, and C. Paul Raj. Biotransformations of R-(+)-pulegone and menthofuran in vitro: Chemical basis for toxicity. Biochem. Biophys. Res. Commun. 173:1086-1092 (1990).
107. K. M. Madyastha, and B. Moorthy. Pulegone mediated hepatotoxicity: Evidence for covalent binding of R-(+)-[14C]pulegone to microsomal proteins in vitro. Chem. Biol. Interact. 72:325-333 (1989).
108. S. C. Khojasteh-Bakht, W. Chen L. L. Koenigs, et al. Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: Evidence for formation of a furan epoxide. Drug Metab. Dispos. 27:574-580 (1999).
109. W. Engel. In vivo studies on the metabolism of the monoterpene pulegone in humans using the metabolism of ingestion-correlated amounts (MICA) approach: Explanation for the toxicity differences between (S)-(-)- and (R)-(+)-pulegone. J. Agric. Food Chem. 51:6589-6597 (2003).
110. W. P. Gordon, A. C. Huitric C. L. Seth, et al. The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran. Drug Metab. Dispos. 15:589-594 (1987).
111. K. M. Madyastha, and C. Paul Raj. Evidence for the formation of a known toxin, p-cresol from menthofuran. Biochem. BiophysRes. Commun. 177:440-446 (1991).