Pathway Taxane Pathway, Pharmacokinetics

Representation of the genes involved in the metabolism and transport of paclitaxel and docetaxel, and the downstream effects of the drugs.
Taxane Pathway, Pharmacokinetics
docetaxel docetaxel paclitaxel paclitaxel paclitaxel docetaxel metaboliteD metaboliteP nr1l2 cyp3a4 slco1b3 cyp2c8 cyp1b1 cyp3a4 cyp3a5 cyp1b1 nr1l2 mapt map4 map2 abcb1 abcc2 abcg2 abcc1
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Description

Taxanes, such as paclitaxel and docetaxel, are widely prescribed chemotherapeutic drugs [Articles:15057285, 15161985, 18068131]. They have been used to treat many forms of cancer including breast, ovarian and lung cancers [Article:15057285]. Paclitaxel was isolated from the Pacific yew in 1971 and docetaxel, a second generation taxane, is a semi-synthetic taxane analogue from the European yew identified approximately 20 years later [Article:15161985]. The pathway above depicts the known candidate pharmacogenes involved in the pharmacokinetics and pharmacodynamics of taxanes.

Microtubules display a form of non-equilibrium dynamics referred to as dynamic instability that is essential to cell division [Article:18068131]. Dynamic instability is regulated by microtubule- associated proteins (MAPs) including MAPT, MAP2 and MAP4 [Article:18068131]. In an un-phosphorylated state, the MAP proteins bind and stabilize microtubules, leading to cell death [Article:18068131].

Microtubules are composed of β-tubulin and α-tubulin heterodimers [Article:15057285]. Taxanes block cell division by binding to α-tubulin, stabilizing the microtubules, leading to cell death [Articles:7627725, 15057285]. A 3.5A structure of bovine βαtubulin, with bound paclitaxel, can be found in the Protein Data Bank [Article:10592235], entry 1JFF [Article:11700061]. In addition, in vitro studies have shown taxanes to induce BCL2 phosphorylation and apoptosis, with docetaxel doing so at much lower concentrations than paclitaxel [Articles:9000560, 7753834].

While paclitaxel and docetaxel share many common structural features, their pharmacology and pharmacokinetics differ somewhat. Consequently, in some patients, solid tumors with resistance to paclitaxel have been shown to be sensitive to docetaxel [Articles:9779713, 10894873].

The pharmacokinetics of taxanes are complex and are complicated by their different formulations 11392447. Both taxanes are primarily metabolized in the liver and their primary route of elimination of the parent drug and hydroxylated metabolite is through biliary excretion via feces [Article:15161985]. Early work found that docetaxel had linear pharmacokinetics but paclitaxel did not [Articles:15161985, 7799018] . However, the two taxanes have different formulations: paclitaxel is dissolved in Cremophor EL (CrEL, poly-oxyethyleneglycol triricinoleate 35)/ethanol (1:1) where as docetaxel is dissolved in polysorbate 80 (Tween 80) 12844327. Tween 80 was found to alter the fraction of unbound docetaxel in patients 12844327 and another study found that in the absence of CrEL the bioavailability of intraperitoneal paclitaxel was significantly increased 11948138. Various other studies have shown that CrEL alters the pharmacokinetic behavior of many drugs, including paclitaxel 12844327, 11527683. Finally, a small study of the recently available, 130-nm albumin-bound (nab) particle formulation of paclitaxel,, devoid of solvents, found that the disposition of paclitaxel is subject to considerable variability, depending upon the formulation used 18594000.

Both paclitaxel [Articles:9492385, 7473140] and docetaxel [Articles:9492385, 15116057, 10092957, 9825831] are metabolized by CYP3A4. Paclitaxel is also metabolized by CYP2C8 [Articles:11668219, 11901098], while docetaxel is also metabolized by CYP3A5 [Article:9825831]. In an in vitro study, a highly significant induction level of PXR (gene NR1I2) -mediated CYP3A4 expression was observed for paclitaxel, whereas docetaxel only moderately increased CYP3A4 expression [Article:18839173]. In another study, paclitaxel activated PXR, but docetaxel did not 11329060. Paclitaxel was also found to activate PXR and enhances P-glycoprotein (ABCB1) mediated drug clearance 11329060 and ABCB1 expression 15650019 as well as CYP2C8 expression 15933212.

Both paclitaxel and docetaxel are substrates for the ATP binding cassette multidrug transporters ABCB1, ABCG2, ABCC1 and ABCC2 [Articles:12608532, 11059771, 9610729, 12417570, 14617793, 17062689, 15849751]. OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel [Article:18509327] and identified as a key regulator of paclitaxel hepatic uptake 16210916, 17186002. OAT2 (SLC22A7) was found to transport paclitaxel in in vitro experiments 15901346.

Taxane resistance is frequent [Articles:17216190, 18068131, 15720262]. Possible mechanisms for such resistance are many, but definitive data for the causes of resistance remain unclear. There are several genes that encode β- and α-tubulins and different tubulins also arise from different post-translational modifications [Article:9348671]. Such structural diversity makes comparative analysis between tubulins in drug-sensitive and drug-resistant cell lines difficult [Article:14556633]. Exposure to taxane creates somatic mutations in tubulins, but the relationship of somatic mutations to resistance remains unclear, even for those mutations near the taxane binding site [Article:19455242]. While an early study found a relationship between mutations in the tubulin-encoding TUBB gene and paclitaxel treatment response and clinical outcome (in tissue samples of patients with advanced non-small-cell lung cancer) 10561216, numerous other genetic and mutational analysis of the gene in cell lines and patients with lung cancer, breast cancer and ovarian cancer did not find such a relationship 11752014, 11750707, 12011233, 12209967, 12893435, 16095531,16002208, 12209587, 12826311, 12680167, suggesting that mutations in TUBB do not play a role in taxane resistance. Genetic and mutational analysis of the TUBB gene has been complicated due to the presence of several pseudogenes with high homology to the wild type gene 12826311, 12209587. Increased expression level of tubulins as a mechanism for resistance remains contradictory, although there growing evidence that this does lead to resistance for particular tubulins [Article:19455242]. Recently, high levels of chromosomal instability, and the genes involved in this instability, have been found to be related to taxane resistance [Article:19458043]

Pharmacogenetics

The impact of genetic variants on taxane response is unclear: several studies did not find relationships between polymorphisms of genes in the taxane pathway, while others did. For example, in a large study (n=914) of ovarian cancer patients from the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) phase III trial who were treated at presentation with carboplatin and taxane regimens, no association between polymorphisms of genes in the pathway and taxane response was found [Article:17925548]. This study assessed polymorphisms in 11 genes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and found no reproducible significant associations between genotype and outcome or toxicity [Article:17925548]. Similarly, in two other studies, no significant association was seen between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance or ABCB1, CYP2C8, CYP3A4 and CYP3A5 and paclitaxel clearance [Articles:17224914, 16299241].

In contrast, other studies of genes in the taxane pathway did find associations between polymorphisms of the genes and either patient survival or drug response. With respect to survival, one study found rs1056836, CYP1B1*3 (4326 C>G; L432V) allele, was significantly associated with progression-free survival, independent of paclitaxel clearance [Article:17224914]. The same SNP was also associated with survival in patients receiving docetaxel [Article:18187806]. In a recent study of patients with metastatic breast cancer, the synonymous variant rs1045642 (ABCB1: 3435 C>T), showed a significantly lower disease control rate and lower overall survival rate than the CC genotype for the variant allele [Article:18836089].

Other small studies have found associations between variants of ABCB1 and taxane pharmacokinetics.. One small study of Japanese patients found associations with ABCB1 polymorphisms, including paclitaxel pharmacokinetics and ABCB1 variants [Article:16803472]. Another small study of Japanese patients found that those with the ABCB1:3435C>T (rs1045642) allele had a significantly higher AUC of a paclitaxel metabolite when compared to those possessing the 3435C allele[15901749]. Other studies associated ABCB1: 2677G>T/A with response to paclitaxel [Article:16467099] , response to taxane- and platinum-based chemotherapy [Article:19203783] and gastrointestinal toxicity [Article:19203783]. A combination of ABCB1:2677G>T/A and ABCB1:3435C>T (rs1045642) genotypes have been associated with neutropenia from paclitaxel therapy [Article:16950614]. A recent small study of Caucasian patients found that the interindividual variability in paclitaxel clearance to be related to variants in ABCB1; in particular, patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants 19143748.

That same study found variability in paclitaxel clearance to also be related to CYP2C8 genotype; the CYP2C8*3 had lower clearance of paclitaxel 19143748.. Another recent small study of docetaxel clearance found greater clearance with patients with the CYP3A4*1B and CYP3A5*1A alleles [Article:18509327]. Most of these findings remain to be validated.

Authors: Connie Oshiro, Sharon Marsh, Howard McLeod, Michelle Carrillo, Teri Klein, Russ Altman.
Citation:
Oshiro Connie, Marsh Sharon, McLeod Howard, Carrillo Michelle, Klein Teri, Altman Russ. "Taxane Pathway" Pharmacogenetics and genomics (2009).
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History:
Therapeutic Categories:
  • Anticancer agents