Article Figures & Data
Figures
- FIG. 1.
Components of eukaryotic genes in which functional SNPs may reside and alter the expression levels and form of the encoded protein.
- FIG. 2.
A schematic diagram of drug disposition and the physiological factors that play roles in drug pharmacokinetics, such as transporters, metabolizing enzymes, protein binding, and gastric acid excretion (data from references 39, 143, 153, 164, 199, and 248). Any variation in genes encoding proteins involved in the disposition of drugs may have an impact on drug pharmacokinetics. NTCP, sodium-dependent taurocholate transporting polypeptide; BSEP, bile salt export pump; PGT, prostagladin transporter; cAMP, cyclic AMP; NAT, N-acetyltransferase; UGT, UDP-glucuronosyl transferase. The exact localizations and efflux directions of some of these transporters are still under investigation.
- FIG. 3.
Two-dimensional (2D) structure of P-gp showing the distribution of coding SNPs (black-filled circles) (229). The amino acid substitutions are presented, together with nucleotide changes (in parentheses). At the top, 28 exons of the MDR1 (ABCB1) gene are shown with the cDNA nucleotide and amino acid positions, together with noncoding SNPs at the promoter, introns, and untranslated regions. The region of P-gp encoded by a given exon is also highlighted in similar shading on the predicted 2D P-gp structure. The positions of the polymorphisms correspond to the positions of MDR1 (ABCB1) cDNA, with the first base of the ATG start codon set to 1. Mutations located in introns are given as the position downstream (−) or upstream (+) of the respective exon according to the genomic organization of MDR1 (ABCB1) (41). wob., wobble. (Modified from reference 3 by permission from Macmillan Publishers Ltd.)
- FIG. 4.
Influence of the CYP2C19 (allele *2) genotype on average steady-state plasma voriconazole concentrations as determined by a population pharmacokinetics analysis. The box-and-whisker plots display the box locations of the median, upper, and lower quartiles, with whiskers extending to the furthest data point within 1.5 times the interquartile range. The scatter of individual data is also displayed. (Reprinted from reference 78).
Tables
- TABLE 1.
Pharmacokinetic characteristics of antifungal drugs in humans
Antifungal agent GI absorption (%) Distribution (vol, % binding) Metabolism (%) Excretion (%) Renal Hepatobiliary Amphotericin B <10 4 liters/kg, 91-95 Minimal 20.6 (parent drug) 42.5 (parent drug) Itraconazole 55-92 11 liters/kg, >99 >80 (oxidation, deakylation) <0.03 (parent drug) 3-18 (parent drug) 35 (metabolites) 54 (metabolites) Fluconazole >80 0.7 liter/kg, 11-12 <20 80 (parent drug) Minimal 11 (metabolites) Voriconazole >90 4.6 liters/kg, 58 >98 (N-oxidation) <2 (unchanged) 20 (metabolites) 80 (metabolites) Posaconazole 8-48 5 liters/kg, 98-99 Minimal (oxidation, glucuronidation) 14 (mostly metabolites) 77 (mostly parent drug) Terbinafine 70-80 11 liters/kg, >99 >99 (N-demethylation, alkyl oxidation, aryl oxidation, hydrolysis) 80 (metabolites) 20 (metabolites) Caspofungin <0.2 0.2 liter/kg, 96 >98.6 (hydrolysis, acetylation) 1.4 (parent drug) 41 (metabolites) 35 (metabolites) Micafungin Poor 0.2 liter/kg, 99.8 >99 (arylsulfation, catechol O-methylation) 0.7 (unchanged) 7.4 (mostly metabolites) >90 (mostly metabolites) Anidulafungin Poor 0.6 liter/kg, 84 >90 (not metabolized enzymatically) <10 (unchanged) Minimal >90 (degradation products) Flucytosine 76-89 0.6 liter/kg, <5 <1 >90 (parent drug) Minimal 1 (metabolites) - TABLE 2.
SNPs affecting lipoprotein metabolisma
Geneb SNP name Position Nucleotide exchange Frequency (%) Effectc CETP 1405V Exon 14 G+16A 32.9 ↑HDL Taq1B Intron 1 G+279A 41.3 ↑HDL LPL S477X Exon 9 C/G 11 ↓TG, ↑HDL HindIII Intron 8 ↓TG APOA-I M1 site Promoter (−76) A/G M2 site Promoter (−83) C/T 55.6 ↓LDL M2 site Promoter (−83) G/A APOA-IV His306Glu G/T 7-9 ↓HDL APOB Arg3611Gln Exon 26 11-46 ↑LDL Glu4154Lys Exon 29 11-46 ↑LDL Thr→Ileu Exon 4 11-46 ↑LDL APOC3 Promoter (−455) T/C ↓TG Nucleotide 1100 C/T ↑TG SstI 3′ untranslated region C/G 14 ↑TG APOE Cys112Arg Exon 3 T/C 15 ↑LDL Arg158Cys Exon 3 C/T 2 ↓LDL HL Promoter (−480) C/T ↑HDL FABP-2 Ala54Thr Exon 2 G/A 27-29 ↑FA LDLr PvuII Intron 16 A/G ↑LDL - TABLE 3.
Human transporter proteins
Transporter Gene Chromosome Size (aa)a Tissue distributionb Membrane localizationc P-gp (MDR1) ABCB1 7q21.1 1,280 Ubiquitous A MRP1 ABCC1 16p13.1 1,531 Ubiquitous (low in L) BL MRP2 ABCC2 10q24 1,545 L, K, I A MRP3 ABCC3 17q22 1,527 L, A, P, K, I BL MRP4 ABCC4 13q32 1,325 Pr, Lu, M, P, T, O, Bl, G A MRP5 ABCC5 3q27 1,437 Ubiquitous BL MRP6 ABCC6 16p13.1 1,503 L, K BL? MRP7 ABCC10 6p21.1 1,492 L, Lu, M ? BCRP ABCG2 4q22 655 Pl, L, I, Br A OATP-A SLCO1A2 12 670 B, L BL OATP-B SLCO2B1 11q13 709 K, L, B, I BL OATP-C SLCO1B1 12p 691 L, Pl BL OATP-D SLCO3A1 15q26 710 Ubiquitous ? OATP-E SLCO4A1 20q13.33 722 Ubiquitous BL? OATP-F SLCO1C1 12p12.3-p14.3 712 B, T ? OATP8 SLCO1B3 12p12 702 L BL OATPRP4 SLCO5A1 8q13.1 848 ? ? OCT1 SLC22A1 6q26 554 L, K (low), I (low) BL OCT2 SLC22A2 6q26 555 K, B, Pl, I (low), S (low) BL OCT3 SLC22A3 6q26-q27 556 L, I, H BL OCTN1 SLC22A4 5q31.1 551 K, L, Lu, I A OCTN2 SLC22A5 5q31 557 B, K, M, Pr, Pl A, BL OAT1 SLC22A6 11q13.1-q13.2 550 K BL OAT2 SLC22A7 6p21.1-p21.2 546 L, K (low) A OAT3 SLC22A8 11q11 542 K, B (low) BL OAT4 SLC22A9/A11 11q13.1 552 K, Pl A OAT5 SLC22A10 11q12.3 541 L A PEPT1 SLC15A1 13q33-q34 708 K, I, L, Pl A, BL PEPT2 SLC15A2 3q13.3-q21 729 K, B A, BL CNT1 SLC28A1 15q25-26 649 K, I, L A CNT2 SLC28A2 15q15 658 Ubiquitous A, BL - TABLE 4.
Major human drug-metabolizing cytochrome P450 enzymesa
CYP Chromosome Expression Relative protein abundance in liver (%) % of drugs metabolized by enzyme (antifungal drugs) Major variant allele(s) Mutation Consequence CYP1A1 15q22-q24 Inducible <1 CYP1A1*2A&B 3801T>C I462V Increased inducibility Increased activity CYP1A2 15q22qter Inducible 8-15 11 (terbinafine) CYP1A2*1F −164C>A Higher inducibility CYP2A6 19q13.2 Constitutive 5-12 3 CYP2A6*2 L160H Inactive enzyme CYP2A6*4 Gene deletion No enzyme CYP2A6*9 TATA-mut Less enzyme CYP2B6 19q13.2 Inducible? 1-5 3 CYP2B6*5 R487C Less enzyme CYP2B6*7 Q172H; K262R; R487C Less enzyme CYP2C8 10q24.1 Constitutive 10 CYP2C8*2 1269F Decreased activity CYP2C8*3 R139K, K399R Decreased activity CYP2C8*4 1264M Decreased activity CYP2C9 10q24 Constitutive 15-20 16 (voriconazole, terbinafine) CYP2C9*2 R144C Reduced affinity for P450 reductase CYP2C9*3 I359L Altered substrate specificity CYP2C19 10q24.1-q24.3 Constitutive <5 8 (voriconazole, terbinafine) CYP2C19*2 Altered splice site Inactive enzyme CYP2C19*3 Stop codon Inactive enzyme CYP2D6 22q13.1 Constitutive 2 19 CYP2D6*2xn Gene duplication Increased activity CYP2D6*4 Defective splicing Inactive enzyme CYP2D6*5 Gene deletion No enzyme CYP2D6*6 1707T>del P34S No enzyme CYP2D6*10 S486T T107I Unstable enzyme CYP2D6*17 R296C S486T Reduced affinity for substrates CYP2E1 10q24.3-qter Constitutive/inducible 7-11 4 CYP2E1*2 R76H Less enzyme expressed CYP2E1*3 V389I No effects CYP2E1*4 V179I No effects CYP3A4 7q21.1 Constitutive 30-40 36 (itraconazole, ketoconazole, voriconazole, terbinafine) CYP3A4*2 S222P Higher Km for substrate CYP3A4*3 M445T Unknown CYP3A4*4 I118V Decreased CYP3A4*5 P218R Decreased CYP3A4*6 831 insA Decreased CYP3A5 7q21.1 Constitutive <1 CYP3A5*3 Splicing defect No enzyme CYP3A5*6 Splicing defect No enzyme ↵ a Modified from reference 68 with permission of the publisher and from reference 215 with permission of Elsevier; includes data from http://www.cypalleles.ki.se .
- TABLE 5.
Potential targets for analyzing genetic polymorphisms important for pharmacokinetics of antifungal drugsa
Drug Absorption Distribution Metabolism Excretion GI pH (ATPase) Efflux drug transporters (P-gp, MRP1+0 -5, BCRP) Albumin AAG Lipoproteins Phase I (CYP450) Phase II (NAT, UGT) Renal (OATs, MRPs, OCTs) Hepatobiliary (P-gp, MRPs, OATPs, OCTs) Triazoles Itraconazole + + + − − + − − − Fluconazole − + − + − − − + − Voriconazole − + ? ? − + − − − Posaconazole + + + ? ? + (?) + (?) − + Polyenes Amphotericin Bb − + + + + − − + + Allylamines Terbinafine − + + + + + − − − Echinocandins Caspofungin − + + − − + + − − Micafungin − ? + − − − + − − Anidulafungin − ? + − − − − − − Pyrimidines Flucytosine − + − − − − − − −
