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Age-and Region-Dependent Disposition of Raloxifene in Rats

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Abstract

Purpose

Raloxifene undergoes extensive glucuronidation in the gastrointestinal (GI) tract and the liver. However, the impact of age on raloxifene disposition has never been studied. The purpose of this paper is to determine glucuronidation and Pharmacokinetics (PK) profiles of raloxifene in rats at different ages.

Methods

Raloxifene glucuronidation was characterized using S9 fractions prepared from different intestinal segments and the liver of F344 rats at 4-, 11-, and 28-week. PK studies were conducted to determine raloxifene oral bioavailability at different ages. Raloxifene and its glucuronides were quantified using LC-MS/MS.

Results

Raloxifene-6-glucuronide and raloxifene-4′-glucuronide were detected as the major metabolites and the ratio of these two glucuronides were different ranging from 2.1 to 4.9 folds in the ileum, jejunum, liver, and duodenum, and from 14.5 to 50 folds in the colon. The clearances in the duodenum at 4-week for both two glucuronides were significantly lower than those at the other two ages. PK studies showed that the oral bioavailability of raloxifene is age dependent. The absolute oral bioavailability of raloxifene was 3.5-folds higher at 4-week compared to that at 11-weeks. When raloxifene was administered through IV bolus, its half-life was 5.9 ± 1.16 h and 3.7 ± 0.68 h at 11-and 4-week, respectively.

Conclusion

These findings suggested that raloxifene metabolism in the duodenum was significantly slower at young age in rats, which increased the oral bioavailability of raloxifene. At 11-week, enterohepatic recycling efficiency was higher than that of 4-week. Raloxifene’s dose at different ages should be carefully considered.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by a grant from the National Institute of General Medical Sciences (1R15GM126475-01A1) and Cancer Prevention Research Institute of Texas (CPRIT, RP190672) for Song Gao. This work was also made possible, in part, by services provided from GCC Center for Comprehensive PK/PD and Formulation (CCPF) with CPRIT grant number of RP180748 and National Institute of Minority Health and Health Disparity (U54MD007605) for Dong Liang.

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Author notes

  1. Ting Du and Rongjin Sun contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne St, Houston, Texas, 77004, USA

    Ting Du, Imoh Etim, Dong Liang & Song Gao

  2. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 4901 Calhoun Street, Houston, Texas, 77204, USA

    Rongjin Sun, Zicong Zheng & Ming Hu

Authors
  1. Ting Du
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  2. Rongjin Sun
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  3. Imoh Etim
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  4. Zicong Zheng
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  5. Dong Liang
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  6. Ming Hu
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  7. Song Gao
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Correspondence to Ming Hu or Song Gao.

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Du, T., Sun, R., Etim, I. et al. Age-and Region-Dependent Disposition of Raloxifene in Rats. Pharm Res 38, 1357–1367 (2021). https://doi.org/10.1007/s11095-021-03084-y

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  • DOI: https://doi.org/10.1007/s11095-021-03084-y

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