Coffee, in different preparations, is widely consumed throughout the world, and contains high levels of phenolic compounds. A single serving provides between 20 and 675 mg of chlorogenic acids depending on the type of roast and the volume consumed and regular consumers an easily have an intake in excess of 1 g per day [10
]. Chlorogenic acids are a group of compounds comprising hydroxycinnamates, such as caffeic acid, ferulic acid, and p
-coumaric acid, linked to quinic acid to form a range of conjugated structures known as caffeoylquinic acids (CQA), feruloylquinic acids (FQA), and p
-coumaroylquinic acids all of which exist in several isomeric forms [10
]. As well as these compounds coffee also contains dicaffeoylquinic acids and caffeoylquinic acid lactones (CQAL) ().
Structures of chlorogenic acids occurring in coffee.
The literature describing the catabolism of coffee chlorogenic acids in human subjects is scarce and, in some instances, contradictory. A study by Nardini et al.
] observed an increase of conjugated caffeic acid in plasma after the ingestion of 200 mL of coffee, while Rechner et al.
] detected ferulic acid, isoferulic acid, dihydroferulic acid, 3-methoxy-4-hydroxybenzoic acid, hippuric acid and 3-hydroxyhippuric acid in urine from five human subjects after three ingestions of two cups of coffee at 4-h intervals. Monteiro et al.
] reported the presence of unmetabolised CQAs in human plasma at a mean peak plasma concentration (Cmax
) of 7.7 µmol/L 2.3 h (Tmax
) after acute ingestion of coffee containing 3,395 µmol of CQAs. Despite the high Cmax
of the CQAs, chlorogenic acids were not detected in urine collected 0–24 h after coffee intake. However, in a subsequent study by the same group, in which human volunteers consumed a coffee containing a much lower 451 µmol of chlorogenic acids, 4- and 5-O
-CQAs were detected in sulfatase/glucuronidase-treated urine from some, but not all, subjects [14
The most recent and detailed research on the fate of chlorogenic acids after the ingestion of coffee is that of Stalmach et al.
] who in studies with healthy humans and ileostomists, in which analysis comprised HPLC-MS2
-based methodology, noted that during passage through the body extensive metabolism of chlorogenic acids occurs with some compounds being absorbed in the small intestine and others in the colon. The plasma pharmacokinetic profiles of circulating chlorogenic acids and their metabolites observed with healthy subjects with a functioning colon, after the ingestion of 412 µmol of chlorogenic acids are illustrated in . Maximum Cmax
values ranged from 6 nmol/L for 5-FQA to 385 nmol/L for dihydroferulic acid, with the duration for Tmax
extending from 0.6 h (ferulic acid-4-O
-sulfate) to 5.2 h (dihydroferulic acid). The compounds detected in highest concentrations in plasma were free and sulfated conjugates of dihydroferulic acid and dihydrocaffeic acid acid with Cmax
values ranging from 41 to 385 nmol/L. The Tmax
for these compounds was in a narrow range from 4.7 to 5.2 h, indicating absorption in the large intestine. Much shorter Tmax
values of 0.6 to 1.0 h, indicative of small intestine absorption, were obtained with 5-O
-CQA, two CQLA-O
-sulfates and three FQAs, all of which had relatively low Cmax
values (). As noted by Stalmach et al.
] most of the chlorogenic-derived compounds were rapidly removed from the circulatory system with elimination half-life (T1/2
) values of 0.3 to 1.9 h. The only compounds with an extended T1/2
were dihydroferulic acid-4-O
-sulfate (4.7 h), dihydroferulic acid-3-O
-sulfate (3.1 h) and ferulic acid-4-O
-sulfate which had an unusual biphasic plasma profile with dual Tmax
values at 0.6 h and 4.3 h. The only unmetabolised compounds detected in plasma were three FQAs () and trace concentrations of 5-O
–2.2 nmol/L; Tmax
–1.0 h). It is also of note that the free acid, dihydroferulic acid, as opposed to the more typical glucuronide and sulfate metabolites, was the principal component to accumulate in plasma which also contained dihydrocaffeic acid in a lower concentration ().
The ileostomists drank a coffee with a very similar 385 µmol chlorogenic acid profile to that ingested by the health subjects [16
]. Plasma was not investigated but analysis of the 0–24 h ileal fluid revealed the presence of 275 µmol of chlorogenic acids mainly, but not exclusively, as unmetabolised compounds. This indicates that ca.
30% of the chlorogenic acids were absorbed in the small intestine of the ileostomists and that in subjects with a functioning colon ca.
70% of intake will pass from the small to the large intestine.
The quantities of chlorogenic acids and their metabolites excreted in urine by healthy subjects and ileostomists over a 24 h period post-ingestion of coffee are summarised in . The healthy volunteers excreted a total of 120.2 µmol which corresponds to 29.2% of intake while urine from ileostomists contained 30.8 µmol which equates with only 8.0% of the ingested chlorogenic acids. This highlights the importance of the colon in the bioavailability of dietary chlorogenic acids.
Plasma pharmacokinetic profiles of circulating chlorogenic acids and metabolites, following the ingestion of 200 mL of coffee by health human subjects.
Urinary excretion of chlorogenic acid metabolites in 0–24 h urine of healthy subjects (n = 11) and ileostomists (n = 5) following the ingestion of 200 mL of coffee.
|Chlorogenic acid and metabolites||Subjects without a colon (385 µmol ingested)||Subjects with a colon (412 µmol ingested)|
|3-O-Caffeoylquinic acid lactone-O-sulfate||0.6 ± 0.1||1.1 ± 0.1|
|4-O-Caffeoylquinic acid lactone-O-sulfate||0.4 ± 0.1||1.0 ± 0.1|
|3-O-Feruloylquinic acid||0.9 ± 0.2||1.2 ± 0.1|
|4-O-Feruloylquinic acid||0.9 ± 0.2||1.1 ± 0.1|
|5-O-Feruloylquinic acid||1.1 ± 0.2||1.0 ± 0.2|
|Ferulic acid-4-O-sulfate||9.9 ± 1.9||11.1 ± 1.6|
|Feruloylglycine||2.1 ± 0.3a||20.7 ± 3.9b|
|Dihydroferulic acid||n.d. a||9.7 ± 2.0b|
|Dihydroferulic acid-4-O-sulfate||0.8 ± 0.2||12.4 ± 3.4|
|Dihydroferulic acid-4-O-glucuronide||n.d.||8.4 ± 1.9|
|Isoferulic acid-3-O-sulfate||0.2 ± 0.0||0.4 ± 0.1|
|Isoferulic acid-3-O-glucuronide||3.9 ± 0.8||4.8 ± 0.5|
|Dihydro-isoferulic acid-3-O-glucuronide||n.d.a||2.5 ± 0.4b|
|Caffeic acid-3-O-sulfate||6.2 ± 1.2||6.4 ± 0.8|
|Caffeic acid-4-O-sulfate||0.6 ± 0.1||0.6 ± 0.1|
|Dihydrocaffeic acid-3-O-sulfate||3.2 ± 0.9a||37.1 ± 8.2b|
|Dihydrocaffeic acid-3-O-glucuronide||n.da||0.7 ± 0.2b|
|Total ||30.8 ± 4.3 (8.0%)a||120.2 ± 17.0 (29.2%)|
The data presented in show that absence of a colon had minimal impact of the excretion of CQAL-O
-sulfates and FQAs, as well as caffeic, ferulic and isoferulic acid-O
-sulfates. Furthermore, the data indicate that the small intestine is most probably the site for i) cleavage of quinic acid from CQAs and FQAs releasing caffeic acid and ferulic acid, (ii) metabolism of caffeic acid to its 3- and 4-O
-sulfates, and ferulic acid to ferulic acid-4-O
-sulfate and iii) the methylation of caffeic acid to form isoferulic acid and its subsequent 3-O
-sulfation and glucuronidation. In contrast, there were major reductions in the excretion of dihydrocaffeic acid-3-O
-sulfate, dihydrocaffeic acid-3-O
-glucuronide, dihydroferulic acid and its glucuronide and sulfated derivatives, dihydro-isoferulic acid-3-O
-glucuronide and feruloylglycine by the ileostomists. This demonstrates that the colon is the site for i) the conversion of ferulic acid to feruloylglycine and dihydroferulic acid and ii) metabolism of caffeic acid to dihydrocaffeic acid which is further metabolised to dihydro-isoferulic acid. Despite its dual plasma Tmax
at 0.6 and 4.3 h in healthy subjects (), urinary excretion of ferulic acid-4-O
-sulfate was unaffected by the absence of a colon () indicating that its secondary plasma Tmax
is not a consequence of colonic absorption. Stalmach et al.
] proposed the data obtained in their coffee feeding studies with healthy volunteers and ileostomists are in keeping with the metabolic routes illustrated in .
Figure 3 Proposed metabolism of chlorogenic acids following the ingestion of coffee by human volunteers. 5-O-CQA and 5-O-FQA are illustrated structures but their respective 3- and 4-isomers would be metabolized in a similar manner and likewise with 4-O-CQAL and (more ...)