Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar


Am J Health Syst Pharm. 2006;63(23):2340-2348. 

In This Article


One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4 enzymes, CYP3A5 enzymes, and PGP efflux pumps. The differences in expression level may be the result of SNPs found on the genes encoding CYP3A4, CYP3A5, and PGP.

One such polymorphism has been identified in the gene encoding for the CYP3A4 enzyme, labeled as CYP3A4*1B, and is found in 46-66% of people from African descent, 4% of Caucasians, and 0% of Asians.[11,12] The SNP presence in the promoter region increases CYP3A4 transcription in vitro.[13] In vivo studies have failed to corroborate these findings, showing no change in the metabolism of known CYP3A4 substrates when the CYP3A4*1B SNP is present. [12] It remains unclear whether the CYP3A4*1B SNP affects the metabolism of CYP3A4 substrates, but the possibility is being examined to determine if the SNP’s presence has any predictive value for drug metabolism.[11,14]

Two distinct polymorphisms have also been found in the gene encoding for CYP3A5. The first, CYP3A5*3, is an SNP in intron 3 that creates a premature stop codon, resulting in protein truncation and inactivation of the CYP3A5 enzyme.[15,16] The second polymorphism, CYP3A5*6, is located in intron 6 and also creates a premature stop codon that decreases transcription of CYP3A5 mRNA.[15] Both of these polymorphisms lead to the inability of an individual to express fully functional CYP3A5. Many other polymorphisms have been identified in the gene that codes for CYP3A5, which prevent its expression, but CYP3A5*3 and CYP3A5*6 are by far the most common.[17] Only individuals with the wild-type gene, CYP3A5*1, produce the enzyme CYP3A5 at a significant level.[16] The CYP3A5*1 polymorphism is present in 10–40% of Caucasians, 33% of Asians, and 55% of African Americans. [17] In patients who express this gene, CYP3A5 accounts for up to 50% of the hepatic CYP3A content and significantly influences the metabolism of CYP3A substrates.[15]

There have been many polymorphisms identified in the MDR1 (ABCB1) gene, which codes for PGP. A cytosine-to-guanine polymorphism found at location 3435 in exon 26 (C3435T) of the MDR1 (ABCB1) gene is found in 16-17% of individuals from African descent, in 50-60% of Caucasians, and in 40-70% of Asians.[18] This change in the genetic code does not result in a substitution in the amino acid sequence and is known as a synonymous SNP.[10,19,20] Even though it is synonymous, this SNP was thought to directly affect the amount of PGP produced, decreasing it two- to fourfold compared with the wild-type SNP in vivo.[7,21] However, other studies have found no relationship between PGP protein production and the presence of the C3435T SNP; therefore, the SNP’s influence on drug metabolism is still controversial.[22] Because the C3435T SNP is silent, it is thought that any influence associated with drug metabolism is due to a link between other polymorphisms in the MDR1 gene.[23] Two such polymorphisms have been identified: one is a synonymous SNP located in exon 12 (C1236T), and the other is a nonsynonymous SNP located in exon 21 (G2677T), which causes a serine-alanine substitution. These polymorphisms were identified in 62% of Caucasians and 13% of African Americans, which correlates with the frequency of the C3435T SNP found in similar populations. Furthermore, the presence of these three linked polymorphisms caused a decrease of 40% in metabolism of a known PGP substrate, suggesting a decrease in the amount of functional PGP produced.[24]

Another polymorphism in the MDR1 (ABCB1) gene is T-129C, which is located in the promoter region and prevents the gene’s transcription. The polymorphism is observed in only 8% of Asians and 10% of Caucasians.[10,23,25] The presence of this SNP correlated with a statistically significant decrease in the amount of PGP produced in human placenta (p < 0.05), which theoretically should decrease metabolism of PGP substrates but this has yet to be demonstrated in a clinical trial.[25]


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