Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Figures & data

Figure 1. Tamoxifen metabolism.

Table 1. Pharmacokinetics parameters of tamoxifen and endoxifen.

		Tmax	Cmax (after one single dose)	Reported mean concentration in steady state as CYP2D6 normal metabolizer	Half-life	Time to steady-state	Metabolism	Excretion	Refs.
Tamoxifen^a		4–7 h [48]	±40^a ng/ml [48]	122 ng/ml [48]	7 days [48]	4 weeks [48]	Hepatic	Feces	[48]
Endoxifen	Endoxifen as metabolite of tamoxifen citrate	N.A.	N.A	10.8 [30]-15.9 [82] ng/ml	N.A	N.A.	Hepatic	Not reported	[30,82]
	Endoxifen as z-endoxifen hydrochloride	2–4 h [23]	64.8^b-635^c ng/ml [23]	146^b-1950^c ng/ml	49^1–68.1^4 hours	7 days [23]	Hepatic [23]	Not reported	[23]

^aWith 20 mg of tamoxifen; ^b With 20 mg of endoxifen;^c With 160 mg of endoxifen ^d with 100 mg of endoxifen; N. A.: not applicable; Refs.: references

Figure 2. Minor enzymes of tamoxifen and endoxifen metabolism.

Table 2. Minor enzymes involved in tamoxifen metabolism.

Gene	Conversion	Comparison	Impact on levels	Refs.
UGT1A4	Tamoxifen to Tamoxifen-N-glucuronide	UGT1A4_48_Val versus UGT1A4 _48_Leu	Higher Tamoxifen-N-glucuronide levels in UGT1A4_48_Val variant	[30,49,50]
CYP3A4 and CYP3A5	Tamoxifen to α-Hydroxy-Tamoxifen		CYP3A4 has a higher implication in the formation of α-Hydroxy-Tamoxifen compared to CYP3A5. α-Hydroxy-Tamoxifen has been postulated to be involved in the adduct formation, which could play a role in the development of endometrial cancer.	[58,59]
CYP2D6 and CYP2B6	Tamoxifen to 4ʹ-hydroxy-tamoxifen		Tamoxifen is metabolized by CYP2D6 and CYP2B6 to 4ʹ-hydroxy-tamoxifen, which might activate a non-apoptotic cytotoxic effect in the endometrium.	[55–57]
FMO1 and FMO3	Tamoxifen to Tamoxifen-N-Oxide		Tamoxifen can be metabolized by FMO1 and FMO3 to Tamoxifen-N-Oxide and it can be metabolized back to Tamoxifen by hemoglobin and NADPH-P450 oxidoreductase. Tamoxifen-N-oxide could behave as repository for Tamoxifen: Tamoxifen-N-Oxide/Tamoxifen ratio is reduced when higher tamoxifen dosages are taken.	[51–53]
				[51–53]
CYP3A4	Tamoxifen-N-Oxide to Tamoxifen			[51–53]

FMO1: flavin monooxygenases 1; FMO3: flavin monooxygenases 3; SULT1A1: Sulfotransferases 1A1 UGT: UDP-glucuronosyltransferases;

Table 3. Minor enzymes involved in endoxifen metabolism.

Endoxifen
Gene	Conversion	Comparison	Impact on levels	Impact on survival outcome	Refs.
UGT1A8	Endoxifen to Endoxifen O-glucuronide	*1/*1 versus *1/*3 or *3/*3	No differences in endoxifen levels (in vitro)		[69]
				No differences in survival	[71]
UGT1A10	Endoxifen to Endoxifen O-glucuronide	*1a versus *2a	No differences in endoxifen levels (in vitro)		[69]
UGT2B7	Endoxifen to Endoxifen O-glucuronide	*1 versus *2	No differences in endoxifen levels		[30,49,60,69,72]
		*1/*1 versus *1/*2 or *2/*2		No differences in survival	[40,71]
SULT1A1	Endoxifen to Endoxifen sulfate	*1/*1 versus *1/*2 versus *2/*2 and copy number variation	No differences in endoxifen levels		[66–68]
		*1/*1 or *1/*2 versus*2/*2		*2/*2: worst OS	[61]
				SULT1A1*2/*2 and UGT2B15*2: worst OS	[62]
		*1/*1 versus *1/*2 and *2/*2		*1/*1:better survival	[63]
		*1/*1 versus *1/2 or *2/* 2 and/or copy number variation		No differences in survival	[64,65]
N-de- methylation	Endoxifen to Norendoxifen	CYP2C19*2	Lower norendoxifen levels		[27]

Table 4. No genetic factors affecting tamoxifen and endoxifen concentrations.

Factor	Comparison	Tamoxifen concentration	Endoxifen concentration	Clinical outcome	Refs.
Age	Young (30–40) versus old (>65 year-old) women	↑	↑^1	Higher concentrations of both metabolites with higher age	[13,75–77]
Gender	Male versus female	?	↓^1	Lower endoxifen concentrations in male patients	[91]
BMI	Higher BMI versus lower BMI (normal)	↓	↓^1	Lower endoxifen concentrations compared to patients with normal BMI (<24.9)	[75,77,82,84]
Season	Winter and other seasons	↓	↓^1	Lower endoxifen concentration levels during winter	[77,88]
Intake moment	Morning versus night	↑	↑^1	15% and 3 % higher endoxifen and tamoxifen systemic exposure after morning intake	[87]
Smoking	Smokers versus non-smokers	-	-	Higher tamoxifen-related nausea, headache and depression in smokers compared to non-smokers	[96]
Total Cholesterol	Total cholesterol before and after at least 1 cycle of treatment	-	-	Lower total cholesterol	[23,74]
LDL cholesterol	LDL cholesterol before and after at least 1 cycle of treatment	-	-	Lower LDL cholesterol	[23,74]
HDL cholesterol	HDL cholesterol before and after at least 1 cycle of treatment	-	-	Lower HDL cholesterol	[23,74]
Triglycerides	Triglycerides before and after at least 1 cycle of treatment	-	-	Lower triglycerides	[23,74]

¹Study as tamoxifen metabolite

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