Dietary supplements such as cranberry, echinacea, garlic, ginseng, saw palmetto and St. John's wort, etc., are commonly taken in many countries around the world. The global dietary supplements market has continued to increase, expecting to reach US$278.02 billion by 2024, according to a new report b...
Dietary supplements such as cranberry, echinacea, garlic, ginseng, saw palmetto and St. John's wort, etc., are commonly taken in many countries around the world. The global dietary supplements market has continued to increase, expecting to reach US$278.02 billion by 2024, according to a new report by Grand View Research, Inc. These products are usually available over the counter and self-administered along with conventional therapeutic drugs, which raise concerns of potential dietary supplement-drug interactions. Most reported dietary supplement-drug interactions are pharmacokinetic interactions that can cause unanticipated adverse reactions or therapeutic failures through inhibition or induction of drug-metabolizing enzymes. Among the drug-metabolizing enzymes, human cytochrome P450 (CYPs) and uridine 5'-diphosphate-glucuronosyltransferases (UGTs) are responsible for the metabolic clearance of more than 90% of drugs. Among the commonly consumed fifty eight dietary supplements readily available in the US market. Many of them have not been carefully assessed for their inhibitory potential on the CYP and UGT activating. In this study, I evaluated the inhibitory potential of twenty four dietary supplements towards nine CYP isoenzymes and that of forty five dietary supplements toward ten UGT isoenzymes in vitro to assess the possibility of their potential for dietary supplement-drug interactions in vivo. I compared in vitro inhibitory potentials of uva-ursi (Arctostaphylos uva-ursi) and its nine individual constituents on the UGT1A1 activity. Additionally, I investigated potential dietary supplement-drug interactions via UGT1A1 inhibition by uva-ursi in vivo. The results show that the tested dietary supplements exhibited different degrees of inhibitory effects on the nine CYP and ten UGT isoenzymes explored. Among the tested twenty four dietary supplements-CYP pairs or forty five dietary supplements-UGT pairs, uva-ursi (Arctostaphylos uva-ursi) had the strongest inhibitory effect on the UGT1A1-mediated β-estradiol-3-glucuronidation in human liver microsomes with an IC50 value of 16.5 ± 2.07 g/mL. Of the nine individual constituents of uva-ursi examined, gallotannin and 1,2,3,6-tetragalloylglucose were found to potently and competitively inhibit UGT1A1 activity with IC50 (Ki) values of 3.65 ± 1.30 M (1.42 ± 0.25 M) and 6.83 ± 1.11 M (4.49 ± 0.41 M), respectively. In addition, the extract of uva-ursi, gallotannin, and 1,2,3,6-tetragalloylglucose strongly inhibited another UGT1A1-catalyzed SN-38 glucuronidation activity in human liver microsomes. The significant inhibition by the extract of uva-ursi of the UGT1A1 activity might be attributable to gallotannin and 1,2,3,6-tetragalloylglucose, at least in part, as its inhibitory pattern was similar. However, the co-administration of oral uva-ursi (1 g/kg) had no effect on the pharmacokinetics of irinotecan, SN-38, SN-38 glucuronide, in rats. Furthermore, the molar metabolic ratio expressed as AUC0‒∞, SN-38 glucuronide / AUC0‒∞, SN-38, which indicates a causal factor evaluating capacities of UGT1A1 activity in vivo, did not show the significant difference for both groups. Gallotannin and 1,2,3,6-tetragalloylglucose were not detectable in plasma at all blood sampling times after oral dosing of uva-ursi 1 g/kg in rats. The poor oral absorption of gallotannin and 1,2,3,6-tetragalloylglucose in uva-ursi might lead to the lack of in vitro-in vivo correlation. This result indicates that concomitant treatment with irinotecan and uva-ursi extracts, does not give rise to significant effects on the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide, and produces practically no clinically significant irinotecan-induced adverse effects. Collectively, my data suggests that the tested various dietary supplements are unlikely to cause clinically significant dietary supplement-drug interactions mediated via inhibition of most CYP and UGT isoenzymes involved in drug metabolism. These findings may provide useful information on dietary supplement-drug interactions and guide the safe use of popularly-consumed dietary supplements. In conclusion, my in vitro/in vivo studies have provided further insights into the interactions of CYPs and UGTs including individual constituents of dietary supplements, which may be useful for the future studies of dietary supplement-CYP pairs, dietary supplement-UGT pairs, and dietary supplement-drug interactions.
Dietary supplements such as cranberry, echinacea, garlic, ginseng, saw palmetto and St. John's wort, etc., are commonly taken in many countries around the world. The global dietary supplements market has continued to increase, expecting to reach US$278.02 billion by 2024, according to a new report by Grand View Research, Inc. These products are usually available over the counter and self-administered along with conventional therapeutic drugs, which raise concerns of potential dietary supplement-drug interactions. Most reported dietary supplement-drug interactions are pharmacokinetic interactions that can cause unanticipated adverse reactions or therapeutic failures through inhibition or induction of drug-metabolizing enzymes. Among the drug-metabolizing enzymes, human cytochrome P450 (CYPs) and uridine 5'-diphosphate-glucuronosyltransferases (UGTs) are responsible for the metabolic clearance of more than 90% of drugs. Among the commonly consumed fifty eight dietary supplements readily available in the US market. Many of them have not been carefully assessed for their inhibitory potential on the CYP and UGT activating. In this study, I evaluated the inhibitory potential of twenty four dietary supplements towards nine CYP isoenzymes and that of forty five dietary supplements toward ten UGT isoenzymes in vitro to assess the possibility of their potential for dietary supplement-drug interactions in vivo. I compared in vitro inhibitory potentials of uva-ursi (Arctostaphylos uva-ursi) and its nine individual constituents on the UGT1A1 activity. Additionally, I investigated potential dietary supplement-drug interactions via UGT1A1 inhibition by uva-ursi in vivo. The results show that the tested dietary supplements exhibited different degrees of inhibitory effects on the nine CYP and ten UGT isoenzymes explored. Among the tested twenty four dietary supplements-CYP pairs or forty five dietary supplements-UGT pairs, uva-ursi (Arctostaphylos uva-ursi) had the strongest inhibitory effect on the UGT1A1-mediated β-estradiol-3-glucuronidation in human liver microsomes with an IC50 value of 16.5 ± 2.07 g/mL. Of the nine individual constituents of uva-ursi examined, gallotannin and 1,2,3,6-tetragalloylglucose were found to potently and competitively inhibit UGT1A1 activity with IC50 (Ki) values of 3.65 ± 1.30 M (1.42 ± 0.25 M) and 6.83 ± 1.11 M (4.49 ± 0.41 M), respectively. In addition, the extract of uva-ursi, gallotannin, and 1,2,3,6-tetragalloylglucose strongly inhibited another UGT1A1-catalyzed SN-38 glucuronidation activity in human liver microsomes. The significant inhibition by the extract of uva-ursi of the UGT1A1 activity might be attributable to gallotannin and 1,2,3,6-tetragalloylglucose, at least in part, as its inhibitory pattern was similar. However, the co-administration of oral uva-ursi (1 g/kg) had no effect on the pharmacokinetics of irinotecan, SN-38, SN-38 glucuronide, in rats. Furthermore, the molar metabolic ratio expressed as AUC0‒∞, SN-38 glucuronide / AUC0‒∞, SN-38, which indicates a causal factor evaluating capacities of UGT1A1 activity in vivo, did not show the significant difference for both groups. Gallotannin and 1,2,3,6-tetragalloylglucose were not detectable in plasma at all blood sampling times after oral dosing of uva-ursi 1 g/kg in rats. The poor oral absorption of gallotannin and 1,2,3,6-tetragalloylglucose in uva-ursi might lead to the lack of in vitro-in vivo correlation. This result indicates that concomitant treatment with irinotecan and uva-ursi extracts, does not give rise to significant effects on the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide, and produces practically no clinically significant irinotecan-induced adverse effects. Collectively, my data suggests that the tested various dietary supplements are unlikely to cause clinically significant dietary supplement-drug interactions mediated via inhibition of most CYP and UGT isoenzymes involved in drug metabolism. These findings may provide useful information on dietary supplement-drug interactions and guide the safe use of popularly-consumed dietary supplements. In conclusion, my in vitro/in vivo studies have provided further insights into the interactions of CYPs and UGTs including individual constituents of dietary supplements, which may be useful for the future studies of dietary supplement-CYP pairs, dietary supplement-UGT pairs, and dietary supplement-drug interactions.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.