599 JPP 2006, 58: 599–604 ß 2006 The Authors Received September 13, 2005 Accepted February 10, 2006 DOI 10.1211/jpp.58.5.0004 ISSN 0022-3573 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA Joshua D. Lambert, Dou Hwan Kim, Ruijin Zheng, Chung S. Yang Correspondence: J. D. Lambert, Department of Chemical Biology, Rutgers, The State University of New Jersey, 164 Frelinghuysen Rd, Piscataway, NJ 08854, USA. E-mail: joshua_lambert@hotmail.com Acknowledgements and funding: This research was supported by NIH CA88961 (to CSY). The authors thank Dr Marc Sturgill for his valuable advice. Note: * These authors contributed equally to this research. Transdermal delivery of (---)-epigallocatechin-3-gallate, a green tea polyphenol, in mice Joshua D. Lambert * , Dou Hwan Kim * , Ruijin Zheng and Chung S. Yang Abstract Epigallocatechin-3-gallate (EGCG) is the most studied catechin in green tea (Camellia sinensis). EGCG and green tea are cancer preventive in many animal models, and numerous mechanisms have been proposed in cell lines. EGCG is poorly bioavailable in man and rodents. We hypothesized that transdermal delivery of EGCG could result in improved bioavailability. Following application of EGCG transdermal gel (50 mg kg 1 , t.d.) to SKH-1 mice, EGCG was observed in the epidermis (1365.7–121.0 ng g 1 ) and dermis (411.2–42.6 ng g 1 ). The maximum plasma concentration (C max ) of EGCG was 44.5 ng mL 1 . The t½ (94.4 h) and AUC 0?24h (881.5 ng mL 1 h) of EGCG were greater than values previously reported for oral EGCG. The t½ and area under the concentration–time curve up to 24 h (AUC 0?24h ) in the liver, small intestine and colon were 21.3–74.6 h and 715–2802 ng g 1 h, respectively. Stability studies showed that the transdermal formulation was stable at 4  C and had a half-life (t½) of 47.1 and 20.2 h at 25  C and 37  C, respectively. These data indicate that transdermal EGCG is useful for delivering prolonged levels of EGCG to plasma and tissues, and may provide an alternative to tea consumption as a dosage form of EGCG. Introduction Epigallocatechin-3-gallate (EGCG, Figure 1) is the most abundant catechin in green tea (Camellia sinensis, (L.) O. Kuntze). EGCG and green tea have been shown to have cancer preventive activity in animal models of oral, oesophageal, intestinal, lung, prostate and other cancers (Higdon & Frei 2003; Lambert & Yang 2003a). In some of these models, EGCG has been shown to inhibit cell prolifera- tion and induce apoptosis. Numerous mechanisms of action for this activity of EGCG have been proposed based on human cancer cell studies (Gupta et al 2001; Liao et al 2004). Due to the limited bioavailability of EGCG following consump- tion of green tea, it is unclear which of these mechanisms are relevant in-vivo (Hou et al 2004). We have previously reported that the absolute bioavailability of EGCG in the mouse and the rat is 26.5 and 1.6%, respectively (Chen et al 1997; Lambert et al 2003). Oral administration of 75 mg kg 1 EGCG to mice resulted in a maximum plasma concentration (C max ) of 140.0 ng mL 1 and half-life (t½) of 82.8 min (Chen et al 1997; Lambert et al 2003). EGCG has been shown to undergo methylation, glucuronidation and sulfation in both rodents and man (Lambert & Yang 2003a; Lu et al 2003; Crespy et al 2004). The major metabolites produced by both the liver and small intestine include 4 0 ,4 0 -di-O-methyl EGCG and EGCG-4 00 -O-glucur- onide. The intestine appears to be a major factor in limiting the bioavailability of orally administered green tea polyphenols in rats (Cai et al 2002). We have found that the mouse intestine has the greatest catalytic efficiency for the glucuronida- tion of EGCG and that human UDP-glucuronosyltransferase (UGT)1A8, an intestine-specific isoform, has high catalytic efficiency (Lu et al 2003). EGCG is also subject to microbial degradation in the colon, resulting in the formation of valerolactone ring fission products (Li et al 2000; Wang et al 2001). We have shown that EGCG is subject to efflux by multidrug-resistance-related proteins (Mrp)1 and 2 in-vitro (Hong et al 2003). Mrp2, which is highly expressed in the