Table 4. Pharmacogenetic studies of anticancer drugs that undergo glucuronidation.

Anticancer agent	Type of study	UGT allele or genotype	Effect
Tamoxifen	In vitro studies using UGT1A4-, UGT1A8- , UGT1A10- and UGT2B7-overexpressing HK293 cells [118,129] and human liver microsomes [118]	UGT1A1*28/*28	Nonsignificant decreases in O-glucuronidation activity against the trans isomers of 4-hydroxytamoxifen and endoxifen in human liver microsomes with genotypes UGT1A1*28/*28 compared with UGT1A1*1/*1, or UGT1A1*28/*28 and UGT1A1*28/*1 compared with UGT1A1*1/*1 [118]
		UGT1A4*2	No differences in N-glucuronidation activity against tamoxifen, trans-4-hydroxytamoxifen and cis-4-hydroxytamoxifen compared with UGT1A4*1a [129]. No significant association with N-glucuronidation activity of trans-4-hydroxytamoxifen in human liver microsomes [118]
		UGT1A4*3b	Increased activity against N-glucuronidation activity of tamoxifen, trans-4-hydroxytamoxifen and cis-4-hydroxytamoxifen [129]. No significant association with N-glucuronidation activity of trans-4-hydroxytamoxifen in human liver microsomes [118]
		UGT1A8*2	No difference in O-glucuronidation activity against trans-4-hydroxytamoxifen. Small but significant decrease against trans-endoxifen compared with wild-type UGT1A8*1a using cell homogenates [118]
		UGT1A8*3	No O-glucuronidation activity activity against trans-4-hydroxytamoxifen and trans-endoxifen using cell homogenates [118]
		UGT1A10*2a	No difference in O-glucuronidation activity activity against trans-4-hydroxytamoxifen and trans-endoxifen nusing cell homogenates [118]
		UGT2B7*2a	Decreased O-glucuronidation activity against trans-4-hydroxytamoxifen and trans-endoxifen in human liver microsomes and cell homogenates [118]
		UGT2B7*1a/*2a	Nonsignificant decrease of O-glucuronidation against trans-4-hydroxytamoxifen and trans-endoxifen compared with UGT2B7*1a/*1a in human liver microsomes [118]
		UGT2B7*2a/*2a	Significant decrease in of O-glucuronidation against trans-4-hydroxytamoxifen and trans-endoxifen glucuronidation activity compared with UGT2B7*1a/*1a in human liver microsomes [118]
Raloxifene	Study of postmenopausal females treated for osteoporosis [139]	UGT1A1*28	Increased glucuronide levels in UGT1A1*28/*28 carriers compared with UGT1A1*28/*1 or UGT1A1*1/*1. The parent drug concentrations were also increased in individuals with UGT1A1*28/*28 but not significantly [139]
Epirubicin	In vitro study in HEK-293 cell membranes expressing UGT2B7 encoded by UGT2B7*1a and UGT2B7*2a alleles [148]	UGT2B7*2a	No detectable differences in activity compared with UGT2B7*1a [148]
	In vitro study with human livers [149]	UGT2B7 haplotype 4†	Increased enzyme activity and gene expression. Diplotypes containing haplotype 4 had a significant 27% average increase in glucuronidation and more than a fivefold increase in mRNA expression compared with diplotypes without haplotype 4 [149]
	Clinical trial in breast cancer patients receiving adjuvant or neoadjuvant FEC100 every 3 weeks [155]	−161T>C	Reduced clearance and increased severe leukopenia [155]
Flavopiridol	Phase 1 clinical trial of patients with refractory neoplasms taking flavopiridol 1-h intravenous infusion daily [172]	UGT1A1*28	No association with pharmacokinetics or the occurrence and severity of diarrhea and neutropenia [172]
Vorinostat	In vitro study with UGT-overexpressing HEK-293 cell homogenates, human liver microsomes and human colon homogenates [164]	UGT1A7*2	No detectable differences in activity compared with UGT1A7*1a [164]
		UGT1A7*3	No detectable differences in activity compared with UGT1A7*1a [164]
		UGT1A7*4	No detectable differences in activity compared with UGT1A7*1a [164]
		UGT1A8*2	Threefold decrease in activity compared with UGT1A8*1a [164]
		UGT1A8*3	No detectable activity [164]
		UGT1A10*2a	No detectable activity [164]
		UGT2B17*2	Reduced activity, gene expression and enzyme affinity [164]
TAS-103	Phase I clinical trial of weekly TAS-103 in patients with advanced cancer [175]	UGT1A1*28	No correlation with TAS-103, TAS-103 glucuronide or clearance although it may correlate with severe neutropenia at high dose levels [175]

^†UGT2B7 haplotype 4 is defined by −45597G; −6682_−6683A; 372A; IVS1+9_IVS1+10A; IVS1+829T; IVS1+985G; IVS1+999C; IVS1+1250G; 801T; IVS4+185C. FEC100: 5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m²; UGT: Uridine 5′-diphosphoglucuronosyltransferase.