3. Absorption

## 3.1. Conditions affecting absorption

Unlike other flavonoids, catechins exist as aglycone form. Their absorption is not influenced by glucosidase digestion in the small intestine [20]. They can be absorbed directly across the intestinal surface. The absorption depends on the physicochemical properties such as molecular size, steric configuration, solubility, hydrophilicity, pKa, and the presence of galloylated derivatives [21]. The presence of food matrix and drugs in the intestinal cavity also influences the absorption.

delay gastric emptying rate. The delay would subsequently reduce the Cmax (824.2 75.1 ng/ mL for EGCG without food; 231.8 134.3 ng/mL and 218.0 160.0 ng/mL with breakfast and strawberry sorbet) due to prolonging the time to Cmax (Tmax) (60 34.6 min for EGCG

Pharmacokinetics and Disposition of Green Tea Catechins

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On the other hand, lower bioavailability is not due to the elimination difference in the presence of food because the half-life of elimination was not significantly different between empty stomach and with food [36]. Moreover, food components could irreversibly and reversibly interact with catechins to affect their absorption in the proximal region of small intestine [37]. It also increased the viscosity of digestive fluid to reduce the dissolution of catechins [38], and induced bile acid secretion to promote elimination of the absorbed catechins. These are factors causing low oral and variable bioavailability of catechins. Despite catechins being stable in the stomach, the oligomer form of catechins, proanthocyanidins, are hydrolyzed to monomer or dimer in the acidic condition [39]. However, an in vivo study has not shown hydrolyzed

Milk has been reported to reduce catechin absorption [11] due to interaction with protein molecules [40]. Alcohol increased the solubility of catechins but did not increase plasma levels of catechins [41]. Co-administration of butter with tea, on the other hand, could decrease the Cmax of EGCG, EGC, EC, GCG, GC, and ECG by more than 40%. It also prolonged the mean residence times (MRT) of free EGCG, EGC, EC, GC and ECG by more than 40%. However, the levels of total (free and conjugated) catechins were not affected. Butter could modify catechins metabolism by increasing the conjugation in the intestine possibly through increasing the expression of UGT1A1 [42, 43]. Both forms of catechins excreted into feces increased from 124 to 232%. It suggests biliary secretion of EGCG, EGC, EC, GCG, and GC increased in response to lipid absorption. Similarly, obese SD rats with hyperlipidemia also increased fecal excretion of catechins from 0.52–1.3 to 1.2–3.4% when compared to normal rats. Lipids may alter the metabolism and the relative proportions of the microflora in the colon [44] and, subsequently, affect catechin catabolism. Since catechin catabolites have been attributed to many biological activities [45], the consequence of suppressing catechins metabolism remains to be elucidated. Furthermore, lipids can delay the gastric emptying causing Tmax increase [46]. Chocolate

In contrast to a lipid meal, carbohydrate rich meals, could increase the oral bioavailability (AUC) of flavanol by 140% [48]. The bioavailability of EGC and EGCG was significantly enhanced when administered with mixture of GTE (50 mg), sucrose and ascorbic acid (3237.0 and 181.8 pmol\*h/L respectively) comparing to green tea (1304.1 and 61.0 pmol\*h/L plasma respectively) in Sprague Dawley (SD) rats [49]. In addition, green tea mixed with vitamin C and xylitol also improved flavanols absorption in human. The Cmax, Tmax, and AUC of flavanols in plasma were 5980.58 μg/mL, 2.14 h, and 18,915.56 h.μg/mL, respectively comparing to the AUC of green tea control, 13,855.43 h.μg/mL. Sugar also delays gastric emptying, that in turns delays the Tmax [50]. Ascorbic acid and sucrose can improve catechin absorption through suppressing intestinal effluxing the absorbed catechins and stabilizing catechins in the

without food; 120 34.6 and 120 34.6 min with breakfast and strawberry sorbet).

3.2. Absorption in the presence of food

product present in the gastric juice [36].

supplement caused the Tmax delay from 1–2 to 3.2–3.8 h [47].

The oral bioavailability or catechins absorption is usually relatively low [22, 23]. The plasma concentration is usually 5–50 times less than the effective biological active concentrations in many in vitro studies [23]. In one study, green tea extract tablets containing 16.7 mg of EC, 44.9 mg of EGC, 11.1 mg of ECG, and 42.9 mg of EGCG were given to eight human subjects. Their mean maximum plasma levels (Cmax) were 34.7, 60.6, 20.9, and 42.8 ng/mL, respectively [24]. The absorption process of catechins and their metabolites may involve efflux transporters, like multidrug resistance-associated protein 2 (MRP2), in the small intestine resulting in low bioavailability [25]. It has been reported that ungallated catechins were effluxed by MRPs expressed in a Caco-2 monolayer cells model [26]. In human, a non-proportional surge of area under curve (AUC), Cmax, and total and free plasma level of EGCG appeared following increase of oral dosage of a green tea extract (GTE) preparation, Polyphenon E, from 800 to 1200 mg [27]. It was possible that the efflux mechanism was saturated at higher dose causing surge of catechins absorption at high dose.

P-glycoprotein (P-gp) is a transporter or efflux transporter for many molecules including catechins [28, 29]. EGCG can interact with P-gp and affect the absorption of other drugs. On the contrary, co-administration of some drugs can affect the absorption of green tea catechins [30]. Polymorphisms of P-gp in human and in vitro studies were associated with variations of Cmax and AUC of catechins after ingestion of green tea extract [31]. Competitive catechindrug interaction of transporters also reduced plasma concentration of β-blocker nadolol mediated by organic anion-transporter OATP1A2 [32]. Oral catechins absorption can also be affected by food intake. The average maximum free EGCG and EGC plasma concentrations in human, following administration of the GTE Polyphenon E, increased 3.5-fold from the fasting condition. While the total plasma levels of free and conjugated epigallocatechin (EGC) were not affected, the plasma level of total epicatechins was lowered [33]. In addition, the bioavailability of EGCG taken in capsule form was 2.7 and 3.5 times higher from fasting condition than when taken with light breakfast or strawberry sorbet [34].

EGCG is stable in acidic condition as in the stomach but unstable in higher pH in the intestine. After passing through the stomach, the EGCG present in the gastric juice is neutralized by bicarbonate ions secreted by the pancreas in the duodenum where EGCG is degraded rapidly [29, 33]. Only about 1% EGCG can be measured in the small intestines after 1-h incubation [35]. Although the acidic condition in a strawberry sorbet or fruit juice could protect EGCG, the subsequently bicarbonate neutralization still leads to EGCG degradation. In addition, food can delay gastric emptying rate. The delay would subsequently reduce the Cmax (824.2 75.1 ng/ mL for EGCG without food; 231.8 134.3 ng/mL and 218.0 160.0 ng/mL with breakfast and strawberry sorbet) due to prolonging the time to Cmax (Tmax) (60 34.6 min for EGCG without food; 120 34.6 and 120 34.6 min with breakfast and strawberry sorbet).

### 3.2. Absorption in the presence of food

3. Absorption

the absorption.

3.1. Conditions affecting absorption

20 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

surge of catechins absorption at high dose.

when taken with light breakfast or strawberry sorbet [34].

Unlike other flavonoids, catechins exist as aglycone form. Their absorption is not influenced by glucosidase digestion in the small intestine [20]. They can be absorbed directly across the intestinal surface. The absorption depends on the physicochemical properties such as molecular size, steric configuration, solubility, hydrophilicity, pKa, and the presence of galloylated derivatives [21]. The presence of food matrix and drugs in the intestinal cavity also influences

The oral bioavailability or catechins absorption is usually relatively low [22, 23]. The plasma concentration is usually 5–50 times less than the effective biological active concentrations in many in vitro studies [23]. In one study, green tea extract tablets containing 16.7 mg of EC, 44.9 mg of EGC, 11.1 mg of ECG, and 42.9 mg of EGCG were given to eight human subjects. Their mean maximum plasma levels (Cmax) were 34.7, 60.6, 20.9, and 42.8 ng/mL, respectively [24]. The absorption process of catechins and their metabolites may involve efflux transporters, like multidrug resistance-associated protein 2 (MRP2), in the small intestine resulting in low bioavailability [25]. It has been reported that ungallated catechins were effluxed by MRPs expressed in a Caco-2 monolayer cells model [26]. In human, a non-proportional surge of area under curve (AUC), Cmax, and total and free plasma level of EGCG appeared following increase of oral dosage of a green tea extract (GTE) preparation, Polyphenon E, from 800 to 1200 mg [27]. It was possible that the efflux mechanism was saturated at higher dose causing

P-glycoprotein (P-gp) is a transporter or efflux transporter for many molecules including catechins [28, 29]. EGCG can interact with P-gp and affect the absorption of other drugs. On the contrary, co-administration of some drugs can affect the absorption of green tea catechins [30]. Polymorphisms of P-gp in human and in vitro studies were associated with variations of Cmax and AUC of catechins after ingestion of green tea extract [31]. Competitive catechindrug interaction of transporters also reduced plasma concentration of β-blocker nadolol mediated by organic anion-transporter OATP1A2 [32]. Oral catechins absorption can also be affected by food intake. The average maximum free EGCG and EGC plasma concentrations in human, following administration of the GTE Polyphenon E, increased 3.5-fold from the fasting condition. While the total plasma levels of free and conjugated epigallocatechin (EGC) were not affected, the plasma level of total epicatechins was lowered [33]. In addition, the bioavailability of EGCG taken in capsule form was 2.7 and 3.5 times higher from fasting condition than

EGCG is stable in acidic condition as in the stomach but unstable in higher pH in the intestine. After passing through the stomach, the EGCG present in the gastric juice is neutralized by bicarbonate ions secreted by the pancreas in the duodenum where EGCG is degraded rapidly [29, 33]. Only about 1% EGCG can be measured in the small intestines after 1-h incubation [35]. Although the acidic condition in a strawberry sorbet or fruit juice could protect EGCG, the subsequently bicarbonate neutralization still leads to EGCG degradation. In addition, food can On the other hand, lower bioavailability is not due to the elimination difference in the presence of food because the half-life of elimination was not significantly different between empty stomach and with food [36]. Moreover, food components could irreversibly and reversibly interact with catechins to affect their absorption in the proximal region of small intestine [37]. It also increased the viscosity of digestive fluid to reduce the dissolution of catechins [38], and induced bile acid secretion to promote elimination of the absorbed catechins. These are factors causing low oral and variable bioavailability of catechins. Despite catechins being stable in the stomach, the oligomer form of catechins, proanthocyanidins, are hydrolyzed to monomer or dimer in the acidic condition [39]. However, an in vivo study has not shown hydrolyzed product present in the gastric juice [36].

Milk has been reported to reduce catechin absorption [11] due to interaction with protein molecules [40]. Alcohol increased the solubility of catechins but did not increase plasma levels of catechins [41]. Co-administration of butter with tea, on the other hand, could decrease the Cmax of EGCG, EGC, EC, GCG, GC, and ECG by more than 40%. It also prolonged the mean residence times (MRT) of free EGCG, EGC, EC, GC and ECG by more than 40%. However, the levels of total (free and conjugated) catechins were not affected. Butter could modify catechins metabolism by increasing the conjugation in the intestine possibly through increasing the expression of UGT1A1 [42, 43]. Both forms of catechins excreted into feces increased from 124 to 232%. It suggests biliary secretion of EGCG, EGC, EC, GCG, and GC increased in response to lipid absorption. Similarly, obese SD rats with hyperlipidemia also increased fecal excretion of catechins from 0.52–1.3 to 1.2–3.4% when compared to normal rats. Lipids may alter the metabolism and the relative proportions of the microflora in the colon [44] and, subsequently, affect catechin catabolism. Since catechin catabolites have been attributed to many biological activities [45], the consequence of suppressing catechins metabolism remains to be elucidated. Furthermore, lipids can delay the gastric emptying causing Tmax increase [46]. Chocolate supplement caused the Tmax delay from 1–2 to 3.2–3.8 h [47].

In contrast to a lipid meal, carbohydrate rich meals, could increase the oral bioavailability (AUC) of flavanol by 140% [48]. The bioavailability of EGC and EGCG was significantly enhanced when administered with mixture of GTE (50 mg), sucrose and ascorbic acid (3237.0 and 181.8 pmol\*h/L respectively) comparing to green tea (1304.1 and 61.0 pmol\*h/L plasma respectively) in Sprague Dawley (SD) rats [49]. In addition, green tea mixed with vitamin C and xylitol also improved flavanols absorption in human. The Cmax, Tmax, and AUC of flavanols in plasma were 5980.58 μg/mL, 2.14 h, and 18,915.56 h.μg/mL, respectively comparing to the AUC of green tea control, 13,855.43 h.μg/mL. Sugar also delays gastric emptying, that in turns delays the Tmax [50]. Ascorbic acid and sucrose can improve catechin absorption through suppressing intestinal effluxing the absorbed catechins and stabilizing catechins in the lumen. Consistently, there was 6–11 times increase in intestinal uptake of total catechins comparing to green tea control following administered green tea with xylitol/citric acid and xylitol/vitamin C [51].

Besides the effect of food and drug interaction, we found catechins absorption steric and structural dependent [52]. In one study, we fed 550 mg/kg GTE to SD rats. After normalization with the input oral doses, the relative AUC0-20 h of epi-isomers in the plasma was higher than its enantiomers, with the level of EGC > GC, EC > C, and EGCG>GCG. Also, the plasma levels of ungallated catechins (EGC, GC, and EC) were higher than gallated catechins (EGCG, GCG,

and ECG) (Figure 3). Catechins absorption should involve selective mechanisms and different transporters. Moreover, when administrated with another GTE with higher proportion of EGCG orally, the relative AUC of GC is higher than EC while other patterns of the AUC levels remained the same [53]. It indicated that unknown interaction of absorptions between catechins and EGCG promotes catechin absorption. In addition, although EGCG is dominantly present in the GTE, its relative AUC level is very low, suggesting EGCG was not favorably

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Catechins are mainly metabolized by phase 2 conjugation processes through methylation, sulfation, and glucuronidation in the intestine and liver after oral administration. Glucuronidation and sulfation mainly occur in the intestine, whereas glucuronidation, sulfation, and methylation occur in the liver. Some conjugates are further methylated. Glucuronidation and sulfation can increase the polarity of catechins to enhance solubility and facilitate their eliminations through urine. EGCG, EGC and EC glucuronide and sulfate were commonly found in plasma [20, 27]. Omethyl-EGC-O-glucuronides and O-methyl-EC-O-sulfates were found in human urine [54] and

absorbed in the intestine (Figure 4).

Figure 4. Summary of factors influencing the bioavailability and absorption.

4. Metabolism

4.1. Effects of conjugations

Figure 3. Diagrams showing the normalized relative AUC levels of total catechins (conjugated and free form) in ocular fluid and tissues. (a) Relative AUC levels of different catechins in the plasma after normalization by the corresponding input catechin dose in the GTE. Ungallate levels showed higher than gallate derivatives while epimers were higher than non-epimers. (b) Relative AUC levels of catechins in vitreous and aqueous humor. Vitreous humor showed selective to non-epimer but no selectivity on gallated and ungallated catechins. No particular trends of catechins selectivity appeared in aqueous humor. (c) Relative AUC levels of catechins in retina, lens, cornea and choroids-sclera. Adapted from Chu et al. [52].

Figure 4. Summary of factors influencing the bioavailability and absorption.

and ECG) (Figure 3). Catechins absorption should involve selective mechanisms and different transporters. Moreover, when administrated with another GTE with higher proportion of EGCG orally, the relative AUC of GC is higher than EC while other patterns of the AUC levels remained the same [53]. It indicated that unknown interaction of absorptions between catechins and EGCG promotes catechin absorption. In addition, although EGCG is dominantly present in the GTE, its relative AUC level is very low, suggesting EGCG was not favorably absorbed in the intestine (Figure 4).
