Raloxifene glucuronidation

Kemp, D.C., Fan, P.W. and Stevens, J.C. (2002) Characterization of raloxifene glucuronidation in vitro contribution of intestinal metabolism to presystemic... 

The solubility or stability of an internal standard in IS working solution could cause IS response variations. Sometimes, an issue of solubility could appear as an issue of stability [42], For example, high interbatch IS response variation was observed for a method of raloxifene glucuronides based on protein precipitation by acetonitrile containing deuterated raloxifene glucuronides. However, internal standard responses within a batch were relatively stable and no such variations in the responses of the corresponding analytes were observed. It was further noticed that the internal standard responses of a batch appeared to be correlated to the operation speed of the lab technician who performed the batch. The faster a lab technician s speed was, the higher the IS responses of his run were. 

Kemp DC, Fan PW, Stevens JC. Characterization of raloxifene glucuronidation in vitro Contribution of intestinal metabolism to presystemic clearance. Drug Metab Dispos. 2002 30(6) 694-700. 

Absorption - Raloxifene is absorbed rapidly after oral administration with approximately 60% of an oral dose adsorbed. However, presystemic glucuronide conjugation is extensive and absolute bioavailability is only 2%. 

Excretion - Raloxifene is primarily excreted in feces less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates and less than 0.2% is excreted unchanged in urine. 

There are two main types of internal standards. The first ones are stable isotope labeled (SIL) internal standards. They are compounds in which several atoms in the analytes are replaced by their respective stable isotopes, such as deuterium (2H, D or d), 13C, 15N, or 170. Labeling with the first three isotopes are most common, particularly labeling with deuterium (due to less difficulty in synthesis and therefore less expensive). For examples, raloxifene-d4-6-glucuronide was used as the internal standard for the determination of raloxifene-6-glucuronide [5] and 1, 2, 3, 4-13C4 estrone (PCJEl) was used as the internal standard for estrone (El) [6], The usage of stable isotope labeled internal standards in quantitative LC-MS or GC-MS analysis is often termed as isotope dilution mass spectrometry (IDMS) [7],... 

Fig. 15 Response ratio of raloxifene-D4-6-glucuronide to raloxifene-6-glucuronide vs. the delay of usage after the preparation of raloxifene-D4-6-glucuronide in methanol or acetonitrile...

Raloxifene undergoes extensive first-pass metabolism to glucuronide conjugates. It is then eliminated by biliary excretion. The pharmacokinetics of raloxifene have been studied in patients with mild hepatic impairment (Child-Pugh class A) and concentrations were found to be approximately 2.5 times higher than in controls, correlating with the patient s bilirubin concentration [8]. 

Raloxifene is adsorbed rapidly after oral administration and has an absolute bioavailability of about 2%. The drug has a half-life of about 28 hours and is eliminated primarily in the feces after hepatic glucuronidation it does not appear to undergo significant biotransformation by cytochrome p450s (CYPs). 

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