madman
Super Moderator
* Oral testosterone undecanoate (TU) is emerging as a key route of administration due to its better ease of administration; however, it suffers from variable pharmacokinetics and pharmacodynamics. The variability is majorly attributed to intestinal glucuronidation of testosterone to its hydrophilic metabolite, testosterone glucuronide (TG), formed by the polymorphic uridine 5'-diphospho-glucuronosyltransferase 2B17 (UGT2B17).
* A pilot crossover clinical study compared testosterone pharmacokinetics when TU was coadministered with curcumin in men with experimental hypogonadism. The plasma concentration-time area under the curve (AUC1–6h) and the peak plasma concentration (Cmax) for testosterone, representing the absorption phase, significantly increased by 50% and 80%, respectively, when TU was administered with curcumin. These findings suggest that curcumin, a UGT2B17 inhibitor, has the potential to enhance the bioavailability of oral TU.
* The data presented here suggest that the coadministration of TU with a UGT2B17 inhibitor, such as curcumin, enhances its oral bioavailability, with the potential to reduce variability and optimize the safe and effective dosing of oral TU.
* Further clinical investigations with higher doses of curcumin and with other UGT2B17 inhibitors in diverse populations are warranted to validate the UGT2B17 inhibition approach for enhancing oral testosterone replacement therapy.
Table 1
Observed pharmacokinetic parameters of oral TU with and without curcumin coadministration in men with experimental hypogonadism
CI, confidence interval (lower-upper); GM, geometric mean; t1/2, half-life (hours).
Fig. 5 Effect of curcumin coadministration on testosterone pharmacokinetics. (A) Average testosterone plasma concentration (ng/mL) of all subjects. (B–F) Testosterone plasma concentration (ng/mL) in individual participants (#3, 5, 7, 8, and 9). TU alone (T) and TU with curcumin arms (T+C) were compared using a paired t test, with ∗Pvalue = .0465 and $P value = .0506.
Abstract
Hypogonadism, characterized by low testosterone blood levels, affects 3%–5% of males worldwide. Oral testosterone undecanoate (TU) is emerging as a key route of administration due to its better ease of administration; however, it suffers from variable pharmacokinetics and pharmacodynamics. The variability is majorly attributed to intestinal glucuronidation of testosterone to its hydrophilic metabolite, testosterone glucuronide (TG), formed by the polymorphic uridine 5'-diphospho-glucuronosyltransferase 2B17 (UGT2B17). This study investigated the potential of curcumin, as a UGT2B17 inhibitor, to enhance TU bioavailability using a series of in vitro and in vivo studies. In human intestinal microsomes, curcumin inhibited UGT2B17 with an IC50of 58 μM. In LS180 cells, a human intestinal cell line, curcumin reduced TG formation dose-dependently at 10, 25, and 100 μM, and also inhibited the formation of androstenedione at 100 μM. In primary human enterocytes, curcumin (100 μM) significantly reduced TG and androstenedione formation by ∼50%. A pilot crossover clinical study compared testosterone pharmacokinetics when TU was coadministered with curcumin in men with experimental hypogonadism. The plasma concentration-time area under the curve (AUC1–6h) and the peak plasma concentration (Cmax) for testosterone, representing the absorption phase, significantly increased by 50% and 80%, respectively, when TU was administered with curcumin. These findings suggest that curcumin, a UGT2B17 inhibitor, has the potential to enhance the bioavailability of oral TU. Further clinical investigations with higher doses of curcumin and with other UGT2B17 inhibitors in diverse populations are warranted to validate the UGT2B17 inhibition approach for enhancing oral testosterone replacement therapy.
A comprehensive understanding of factors affecting testosterone disposition is essential to develop a safe and effective oral TRT.17 Previous research from our laboratory has demonstrated the critical role of uridine 5'-diphospho-glucuronosyltransferase 2B17 (UGT2B17) in the metabolism of testosterone to its water-soluble metabolite, testosterone glucuronide (TG).18 UGT2B17 is one of the most variable drug-metabolizing enzymes (DMEs), which is predominantly expressed in the intestine. The intestinal abundance of UGT2B17 is more than 5-fold higher compared with its liver abundance.19,20 Variability in UGT2B17 abundance is primarily influenced by copy number variations, but also by some nongenetic factors such as age and sex, all of which could contribute to the poor and highly variable PK of orally dosed testosterone.21 In addition to TG, androstenedione (AED) is another primary metabolite of testosterone, which is formed by 17β-hydroxysteroid dehydrogenase (HSDs). Furthermore, testosterone also undergoes metabolism by CYP3A4, although its overall contribution to the systemic clearance of testosterone is relatively limited.18 Taken together, the variability in testosterone metabolism presents a significant challenge in oral TRT, particularly underscoring the importance of intestinal UGT2B17 to improve oral absorption of testosterone.22
We hypothesized that inhibition of intestinal UGT2B17 (and other intestinal DMEs) could enhance the oral bioavailability of TU. To test this hypothesis, we selected curcumin as a potential inhibitor based on our previous in vitro findings. Curcumin was selected for 2 reasons: (1) its well-established clinical safety profile in humans, as it is widely consumed and tolerated as a dietary supplement and spice23,24 and (2) its potential for a targeted intestinal effect is supported by the expectation of high luminal concentrations at the site of absorption,25,26 where it undergoes rapid local metabolism, further minimizing the risk of systemic toxicity.27 We first evaluated the inhibitory effect of curcumin on testosterone metabolism in vitro using human intestinal microsomes (HIMs), LS180 cells, and cryopreserved human enterocytes. Subsequently, the effect of curcumin on testosterone bioavailability was investigated in vivo in a pilot clinical PK study. The study used oral TU in men with experimental hypogonadism induced via the administration of relugolix, a GnRH antagonist.28 Although the clinical study employed the marketed formulation of TU (a lipophilic prodrug), we used the active drug, testosterone, in our in vitro assays to directly assess the inhibition of UGT2B17-mediated testosterone metabolism, the pharmacologically relevant step. The data presented here suggest that the coadministration of TU with a UGT2B17 inhibitor, such as curcumin, enhances its oral bioavailability, with the potential to reduce variability and optimize the safe and effective dosing of oral TU.
2.9 Clinical PK study design
On day 1, all participants with elevated urinary TG/AG ratios proceeded to the PK study. These men received a 120 mg oral dose of relugolix (Orgovyx), a GnRH receptor antagonist, to suppress endogenous testosterone biosynthesis. On day 2, subjects were administered 237 mg of oral TU (Jatenzo) alone with a meal containing 12 g of fat. On day 3, participants received the identical 237 mg of TU along with a 630 mg of oral curcumin capsule and a meal containing 12 g of fat. Blood samples were collected prior to dosing and at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after dosing on days 2 and 3. Participants were seen again for follow-up to ensure a return to their baseline state.
Discussion
After administration of oral TU with curcumin in men with experimental hypogonadism, AUC0–24h for testosterone showed a 40% increase, although this change was not statistically significant due to the considerable variability in plasma exposure among subjects. This could be due to rapid metabolism of curcumin by intestinal and hepatic cytochrome P450 and UGT enzymes, resulting in a transient inhibitory effect. Notably, AUC1–6h and Cmax exhibited a statistically significant increases when curcumin was coadministered with oral TU. This indicates the curcumin interaction with intestinal UGT2B17 during the absorption phase and no change in the terminal phase. Moreover, in addition to the primary metabolites (TG and AED), the sequential metabolite AG formation was also significantly reduced after coadministration of curcumin, indicating inhibition of both dehydrogenation and glucuronidation pathways. However, the data from the untargeted metabolomics experiment revealed no change in other endogenous steroidal substrates, indicating minimal effect on systemic testosterone metabolism.
The small sample size (n = 5 participants) is one of the limitations of this pilot study, which was the primary reason for nonsignificant changes in AUCR0–24h. Furthermore, relugolix is known to significantly suppress testosterone synthesis for 2–3 days, with testosterone levels typically returning to normal within 6–8 days after discontinuation.55 Our clinical study failed to achieve consistent GnRH clamp by relugolix for all subjects, suggesting variability in relugolix efficacy (Supplemental Fig. 2). Another limitation of our study is that we only enrolled the expressors of UGT2B17, which was chosen to test our hypothesis of blocking UGT2B17 activity in vivo. Further studies could explore curcumin’s effect on testosterone PK in individuals with UGT2B17 gene deletions to better understand its effects on non-UGT-mediated pathways. Although our primary focus was to assess inhibition of UGT2B17, we investigated the potential of curcumin to inhibit HSDs. However, the inhibition of CYP3A4 was not studied, as its fractional contribution (fm) to testosterone metabolism is relatively minor.
In conclusion, the in vitro and in vivo evaluation of the inhibitory potential of curcumin on UGT2B17 demonstrated promising results with respect to testosterone bioavailability enhancement. The increase in testosterone AUC1–6h supports the hypothesis that intestinal UGT2B17 inhibition is achievable. This approach could be extended to other UGT2B17 substrates with poor and variable bioavailability, including investigational oral male contraceptives such as dimethandrolone undecanoate and 11β-methyl-19-nortestosterone as well as anticancer drugs like belzutifan and vorinostat. Future clinical trials are warranted to explore the dose-dependent effects of curcumin in human subjects to optimize the coadministration strategy with oral TU. Similarly, more potent UGT2B17 inhibitors that target intestinal glucuronidation can be developed for bioavailability enhancement of drugs metabolized by intestinal UGTs.
* A pilot crossover clinical study compared testosterone pharmacokinetics when TU was coadministered with curcumin in men with experimental hypogonadism. The plasma concentration-time area under the curve (AUC1–6h) and the peak plasma concentration (Cmax) for testosterone, representing the absorption phase, significantly increased by 50% and 80%, respectively, when TU was administered with curcumin. These findings suggest that curcumin, a UGT2B17 inhibitor, has the potential to enhance the bioavailability of oral TU.
* The data presented here suggest that the coadministration of TU with a UGT2B17 inhibitor, such as curcumin, enhances its oral bioavailability, with the potential to reduce variability and optimize the safe and effective dosing of oral TU.
* Further clinical investigations with higher doses of curcumin and with other UGT2B17 inhibitors in diverse populations are warranted to validate the UGT2B17 inhibition approach for enhancing oral testosterone replacement therapy.
Table 1
Observed pharmacokinetic parameters of oral TU with and without curcumin coadministration in men with experimental hypogonadism
CI, confidence interval (lower-upper); GM, geometric mean; t1/2, half-life (hours).
Fig. 5 Effect of curcumin coadministration on testosterone pharmacokinetics. (A) Average testosterone plasma concentration (ng/mL) of all subjects. (B–F) Testosterone plasma concentration (ng/mL) in individual participants (#3, 5, 7, 8, and 9). TU alone (T) and TU with curcumin arms (T+C) were compared using a paired t test, with ∗Pvalue = .0465 and $P value = .0506.
Abstract
Hypogonadism, characterized by low testosterone blood levels, affects 3%–5% of males worldwide. Oral testosterone undecanoate (TU) is emerging as a key route of administration due to its better ease of administration; however, it suffers from variable pharmacokinetics and pharmacodynamics. The variability is majorly attributed to intestinal glucuronidation of testosterone to its hydrophilic metabolite, testosterone glucuronide (TG), formed by the polymorphic uridine 5'-diphospho-glucuronosyltransferase 2B17 (UGT2B17). This study investigated the potential of curcumin, as a UGT2B17 inhibitor, to enhance TU bioavailability using a series of in vitro and in vivo studies. In human intestinal microsomes, curcumin inhibited UGT2B17 with an IC50of 58 μM. In LS180 cells, a human intestinal cell line, curcumin reduced TG formation dose-dependently at 10, 25, and 100 μM, and also inhibited the formation of androstenedione at 100 μM. In primary human enterocytes, curcumin (100 μM) significantly reduced TG and androstenedione formation by ∼50%. A pilot crossover clinical study compared testosterone pharmacokinetics when TU was coadministered with curcumin in men with experimental hypogonadism. The plasma concentration-time area under the curve (AUC1–6h) and the peak plasma concentration (Cmax) for testosterone, representing the absorption phase, significantly increased by 50% and 80%, respectively, when TU was administered with curcumin. These findings suggest that curcumin, a UGT2B17 inhibitor, has the potential to enhance the bioavailability of oral TU. Further clinical investigations with higher doses of curcumin and with other UGT2B17 inhibitors in diverse populations are warranted to validate the UGT2B17 inhibition approach for enhancing oral testosterone replacement therapy.
A comprehensive understanding of factors affecting testosterone disposition is essential to develop a safe and effective oral TRT.17 Previous research from our laboratory has demonstrated the critical role of uridine 5'-diphospho-glucuronosyltransferase 2B17 (UGT2B17) in the metabolism of testosterone to its water-soluble metabolite, testosterone glucuronide (TG).18 UGT2B17 is one of the most variable drug-metabolizing enzymes (DMEs), which is predominantly expressed in the intestine. The intestinal abundance of UGT2B17 is more than 5-fold higher compared with its liver abundance.19,20 Variability in UGT2B17 abundance is primarily influenced by copy number variations, but also by some nongenetic factors such as age and sex, all of which could contribute to the poor and highly variable PK of orally dosed testosterone.21 In addition to TG, androstenedione (AED) is another primary metabolite of testosterone, which is formed by 17β-hydroxysteroid dehydrogenase (HSDs). Furthermore, testosterone also undergoes metabolism by CYP3A4, although its overall contribution to the systemic clearance of testosterone is relatively limited.18 Taken together, the variability in testosterone metabolism presents a significant challenge in oral TRT, particularly underscoring the importance of intestinal UGT2B17 to improve oral absorption of testosterone.22
We hypothesized that inhibition of intestinal UGT2B17 (and other intestinal DMEs) could enhance the oral bioavailability of TU. To test this hypothesis, we selected curcumin as a potential inhibitor based on our previous in vitro findings. Curcumin was selected for 2 reasons: (1) its well-established clinical safety profile in humans, as it is widely consumed and tolerated as a dietary supplement and spice23,24 and (2) its potential for a targeted intestinal effect is supported by the expectation of high luminal concentrations at the site of absorption,25,26 where it undergoes rapid local metabolism, further minimizing the risk of systemic toxicity.27 We first evaluated the inhibitory effect of curcumin on testosterone metabolism in vitro using human intestinal microsomes (HIMs), LS180 cells, and cryopreserved human enterocytes. Subsequently, the effect of curcumin on testosterone bioavailability was investigated in vivo in a pilot clinical PK study. The study used oral TU in men with experimental hypogonadism induced via the administration of relugolix, a GnRH antagonist.28 Although the clinical study employed the marketed formulation of TU (a lipophilic prodrug), we used the active drug, testosterone, in our in vitro assays to directly assess the inhibition of UGT2B17-mediated testosterone metabolism, the pharmacologically relevant step. The data presented here suggest that the coadministration of TU with a UGT2B17 inhibitor, such as curcumin, enhances its oral bioavailability, with the potential to reduce variability and optimize the safe and effective dosing of oral TU.
2.9 Clinical PK study design
On day 1, all participants with elevated urinary TG/AG ratios proceeded to the PK study. These men received a 120 mg oral dose of relugolix (Orgovyx), a GnRH receptor antagonist, to suppress endogenous testosterone biosynthesis. On day 2, subjects were administered 237 mg of oral TU (Jatenzo) alone with a meal containing 12 g of fat. On day 3, participants received the identical 237 mg of TU along with a 630 mg of oral curcumin capsule and a meal containing 12 g of fat. Blood samples were collected prior to dosing and at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after dosing on days 2 and 3. Participants were seen again for follow-up to ensure a return to their baseline state.
Discussion
After administration of oral TU with curcumin in men with experimental hypogonadism, AUC0–24h for testosterone showed a 40% increase, although this change was not statistically significant due to the considerable variability in plasma exposure among subjects. This could be due to rapid metabolism of curcumin by intestinal and hepatic cytochrome P450 and UGT enzymes, resulting in a transient inhibitory effect. Notably, AUC1–6h and Cmax exhibited a statistically significant increases when curcumin was coadministered with oral TU. This indicates the curcumin interaction with intestinal UGT2B17 during the absorption phase and no change in the terminal phase. Moreover, in addition to the primary metabolites (TG and AED), the sequential metabolite AG formation was also significantly reduced after coadministration of curcumin, indicating inhibition of both dehydrogenation and glucuronidation pathways. However, the data from the untargeted metabolomics experiment revealed no change in other endogenous steroidal substrates, indicating minimal effect on systemic testosterone metabolism.
The small sample size (n = 5 participants) is one of the limitations of this pilot study, which was the primary reason for nonsignificant changes in AUCR0–24h. Furthermore, relugolix is known to significantly suppress testosterone synthesis for 2–3 days, with testosterone levels typically returning to normal within 6–8 days after discontinuation.55 Our clinical study failed to achieve consistent GnRH clamp by relugolix for all subjects, suggesting variability in relugolix efficacy (Supplemental Fig. 2). Another limitation of our study is that we only enrolled the expressors of UGT2B17, which was chosen to test our hypothesis of blocking UGT2B17 activity in vivo. Further studies could explore curcumin’s effect on testosterone PK in individuals with UGT2B17 gene deletions to better understand its effects on non-UGT-mediated pathways. Although our primary focus was to assess inhibition of UGT2B17, we investigated the potential of curcumin to inhibit HSDs. However, the inhibition of CYP3A4 was not studied, as its fractional contribution (fm) to testosterone metabolism is relatively minor.
In conclusion, the in vitro and in vivo evaluation of the inhibitory potential of curcumin on UGT2B17 demonstrated promising results with respect to testosterone bioavailability enhancement. The increase in testosterone AUC1–6h supports the hypothesis that intestinal UGT2B17 inhibition is achievable. This approach could be extended to other UGT2B17 substrates with poor and variable bioavailability, including investigational oral male contraceptives such as dimethandrolone undecanoate and 11β-methyl-19-nortestosterone as well as anticancer drugs like belzutifan and vorinostat. Future clinical trials are warranted to explore the dose-dependent effects of curcumin in human subjects to optimize the coadministration strategy with oral TU. Similarly, more potent UGT2B17 inhibitors that target intestinal glucuronidation can be developed for bioavailability enhancement of drugs metabolized by intestinal UGTs.
