Journal List > Korean J Leg Med > v.39(2) > 1087963

Cho, Han, Shin, An, Yu, Song, and Yoo: A Detailed Analysis of Alcohol Pharmacokinetics in Healthy Korean Men

Abstract

To determine blood alcohol concentration (BAC) by extrapolation, an understanding of basal pharmacokinetics is indispensable. Breath alcohol concentration (BrAC) has been used for the determination of body alcohol concentration replaced by BAC in Korea. Therefore, the determination of BAC/BrAC ratio is a key problem in alcohol pharmacokinetics. Among several factors, the ingested dose of alcohol and the allelic variation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) are the most significant factors influencing the pharmacokinetic parameters, particularly in the absorption and elimination phases. This study shows a detailed pharmacokinetic analysis of BAC and BrAC associated with genetic polymorphism including ALDH2 in 42 healthy Korean men. The change in the alcohol dose ingested influenced the maximum concentration (Cmax), the time to reach Cmax (Tmax), the absorption rate constant (K01), the area under the concentration-time curve (AUClast), and the hourly elimination rate. The conversion of wild-type 487Glu (ALDH2∗1) to 487Lys (ALDH2∗2) in human ALDH2 resulted in changes in Cmax (ALDH2∗1/∗1, 0.03±0.01 g/dL [±standard deviation] vs. ALDH2∗1/∗2, 0.05±0.004 g/dL [P<0.01]), AUClast (ALDH2∗1/∗1, 4.48±2.19 g∙ min/dL vs. ALDH2∗1/∗2, 7.52±1.26 g∙min/dL [P<0.05]), and the BAC elimination rate (ALDH2∗1/∗1, 0.05±0.02 g/L/hr vs. ALDH2∗1/∗2, 0.09±0.01 g/L/hr [P<0.05]). Moreover, the comparison of BAC and BrAC by Bland-Altman plot showed good agreement, suggesting that the measurement of BrAC can be a good alternative for the determination of BAC, particularly in the post-absorption phase. These results provide fundamental information about the pharmacokinetics of alcohol and the determination of BAC in forensics.

REFERENCES

1. Nutt DJ, King LA, Phillips LD, et al. Drug harms in the UK: a multicriteria decision analysis. Lancet. 2010; 376:1558–65.
crossref
2. Kelly AT, Mozayani A. An overview of alcohol testing and interpretation in the 21st century. J Pharm Pract. 2012; 25:30–6.
crossref
3. Jones AW. Evidence-based survey of the elimination rates of ethanol from blood with applications in forensic casework. Forensic Sci Int. 2010; 200:1–20.
crossref
4. Song BJ, Abdelmegeed MA, Yoo SH, et al. Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications. J Proteomics. 2011; 74:2691–702.
crossref
5. Higuchi S, Matsushita S, Muramatsu T, et al. Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese. Alcohol Clin Exp Res. 1996; 20:493–7.
crossref
6. Chen YC, Peng GS, Wang MF, et al. Polymorphism of ethanol-metabolism genes and alcoholism: correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact. 2009; 178:2–7.
crossref
7. Liu J, Zhou Z, Hodgkinson CA, et al. Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations. Alcohol Clin Exp Res. 2011; 35:304–16.
crossref
8. Farres J, Wang X, Takahashi K, et al. Effects of changing glutamate 487 to lysine in rat and human liver mitochondrial aldehyde dehydrogenase. A model to study human (Oriental type) class 2 aldehyde dehydrogenase. J Biol Chem. 1994; 269:13854–60.
9. Zhou J, Weiner H. Basis for half-of-the-site reactivity and the dominance of the K487 oriental subunit over the E487 subunit in heterotetrameric human liver mitochondrial aldehyde dehydrogenase. Biochemistry. 2000; 39:12019–24.
crossref
10. Higuchi S, Matsushita S, Imazeki H, et al. Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet. 1994; 343:741–2.
crossref
11. Chen CC, Lu RB, Chen YC, et al. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet. 1999; 65:795–807.
crossref
12. Wright NR, Cameron D. The influence of habitual alcohol intake on breath-alcohol concentrations following prolonged drinking. Alcohol Alcohol. 1998; 33:495–501.
crossref
13. Jones AW, Andersson L. Comparison of ethanol concentrations in venous blood and end-expired breath during a controlled drinking study. Forensic Sci Int. 2003; 132:18–25.
crossref
14. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health. 2007; 30:5–13.
15. Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006; 29:245–54.
16. Lieber CS. Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev. 1997; 77:517–44.
crossref
17. Lieber CS. The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. Drug Metab Rev. 2004; 36:511–29.
crossref
18. Niederhut MS, Gibbons BJ, Perez-Miller S, et al. Three-dimensional structures of the three human class I alcohol dehydrogenases. Protein Sci. 2001; 10:697–706.
crossref
19. Stone CL, Bosron WF, Dunn MF. Amino acid substitutions at position 47 of human beta 1 beta 1 and beta 2 beta 2 alcohol dehydrogenases affect hydride transfer and coenzyme dissociation rate constants. J Biol Chem. 1993; 268:892–9.
crossref
20. Charlier HA Jr, Plapp BV. Kinetic cooperativity of human liver alcohol dehydrogenase gamma(2). J Biol Chem. 2000; 275:11569–75.
21. Lee SL, Hoog JO, Yin SJ. Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism. Pharmacogenetics. 2004; 14:725–32.
22. Larson HN, Zhou J, Chen Z, et al. Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487. J Biol Chem. 2007; 282:12940–50.
23. Chen YC, Lu RB, Peng GS, et al. Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2∗2 variant gene allele. Alcohol Clin Exp Res. 1999; 23:1853–60.
crossref
24. Peng GS, Chen YC, Tsao TP, et al. Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2∗2 gene allele. Pharmacogenet Genomics. 2007; 17:845–55.
crossref
25. Jones AW, Norberg A, Hahn RG. Concentration-time profiles of ethanol in arterial and venous blood and end-expired breath during and after intravenous infusion. J Forensic Sci. 1997; 42:1088–94.
crossref

Fig. 1.
Mean breath alcohol concentration (BrAC) and blood alcohol concentration (BAC) versus time profiles in group A (0.5 g/kg) and group B (0.8 g/kg) participants. After drinking alcohol within a period of 20 minutes, BrAC and BAC were determined every 30 or 60 minutes (30, 60, 90, 120, 150, 180, 240, 300, 360, and 420 minutes) as described in the Materials and Methods section.
kjlm-39-27f1.tif
Fig. 2.
Bland-Altman plot of each participant's difference (blood alcohol concentration [BAC]-breath alcohol concentration [BrAC]) against the mean of the two measurements ([BAC+BrAC]/2). Empty circles and filled circles represent data from group A (0.5 g/kg) and group B (0.8 g/kg), respectively. The horizontal lines show a mean bias of -0.00075, and 95% lower and upper limits of agreement of -0.1136 and 0.1121.
kjlm-39-27f2.tif
Table 1.
Pharmacokinetic parameters in group A (0.5 g/kg, n=20) and group B (0.8 g/kg, n=22) participants
Parameter Group A (n=20) Group B (n=22)
Breath    
 Tmax (min) 51.00±21.98 77.73±28.77
 Cmax (g/dL) 0.04±0.01 0.06±0.01
 AUClast (g∙min/dL) 5.01±2.25 12.50±3.730
 K01 (1/min) 0.26±0.06 0.42±0.21
 KM (g/dL) 3.76±0.26 3.66±0.31
 VM (1/min) 1.16±0.11 1.22±0.07
 Elimination rate (g/L/hr) 0.06±0.02 0.12±0.03
Blood    
 Tmax (min) 37.50±13.33 80.45±36.32
 Cmax (g/dL) 0.03±0.01 0.06±0.01
 AUClast (g∙min/dL) 5.09±2.36 13.39±3.790
 K01 (1/min) 0.24±0.11 0.45±0.22
 KM (g/dL) 3.71±0.50 3.69±0.42
 VM (1/min) 1.29±0.31 1.21±0.07
 Elimination rate (g/L/hr) 0.06±0.02 0.12±0.03

Values are presented as mean±standard deviation.

Tmax, times to reach Cmax; Cmax, maximum concentrations; AUClast, area under the concentration-time curve; K01, absorption rate constant; KM, Michaelis-Menten constant; VM, maximum elimination rate.

Table 2.
Individual elimination rate (g/L/hr) of breath alcohol concentration and blood alcohol concentration calculated by linear regression
Subject BrAER (g/L/hr) BAER (g/L/hr)
Group A    
1 0.05621 0.06346
3 0.09002 0.08939
4 0.02035 0.01890
5 0.07603 0.08267
6 0.07588 0.08411
11 0.05574 0.05126
12 0.09430 0.08655
14 0.09101 0.07913
15 0.03101 0.02767
16 0.06819 0.05350
17 0.05895 0.05457
19 0.02597 0.02991
26 0.09130 0.07507
27 0.05648 0.04249
28 0.05648 0.05588
29 0.02087 0.02018
32 0.10093 0.09870
33 0.07055 0.08359
34 0.05467 0.04774
37 0.05562 0.05710
Group B    
2 0.11733 0.05994
7 0.08885 0.08245
8 0.15333 0.16091
9 0.08907 0.09739
10 0.09105 0.07435
13 0.09485 0.11400
18 0.11505 0.11612
20 0.14395 0.13333
21 0.15114 0.11176
22 0.12256 0.16537
23 0.11484 0.11114
24 0.10726 0.09690
25 0.12091 0.14696
30 0.15995 0.15785
31 0.11956 0.12306
35 0.08055 0.11785
36 0.08333 0.08058
38 0.14584 0.13710
39 0.12058 0.11530
40 0.15114 0.14416
41 0.15052 0.16384
42 0.12422 0.11703

BrAER, alcohol elimination rate in breath test; BAER, alcohol elimination rate in blood test.

Table 3.
Allelic and genotypic frequencies of ADH1B, ADH1C, and ALDH2 polymorphisms
Genotypic frequency Group A (n=20) Group B (n=22),
ADH1B His47Arg
(rs1229984 SNP, A-to-G polymorphism)
AA 14 (70.0) 08 (36.4)
AG 06 (30.0) 11 (50.0)
GG 0 (0)0. 03 (13.6)
A 34 (85.0) 27 (61.4)
G 06 (15.0) 17 (38.6)
ADH1C Ile349Val    
(rs698 SNP, A-to-G polymorphism)
AA 17 (85.0) 15 (68.2)
AG 03 (15.0) 07 (31.8)
GG 0 (0)0. 0 (0)0.
A 37 (92.5) 37 (84.1)
G 3 (7.5) 07 (15.9)
ALDH2 Glu487Lys    
(rs671, G-to-A polymorphism)
GG 16 (80.0) 21 (95.5)
GA 04 (20.0) 1 (4.5)
AA 0 (0)0. 0 (0)0.
G 36 (90.0) 43 (97.7)
A 04 (10.0) 1 (2.3)

Values are presented as number (%).

Table 4.
Comparison of pharmacokinetic parameters according to the ADH1B, ADH1C, and ALDH2 genotypes in group A participants
Parameter ADH1B (His47Arg, rs1229984, A to G) ADH1C (Ile349Val, rs698, A to G) ALDH2 (Glu487Lys, rs671, G to A)
AA (n=14) AG (n=6) P-valuea) AA (n=17) AG (n=3) P-valuea) GG (n=16) AG (n=4) P-valuea)
Breath
 Tmax (min) 51.42±21.79 50.00±24.49 0.8575 49.41±21.06 60.00±30.00 0.4893 52.50±23.24 45.00±17.32 0.6070
 Cmax (g/dL) 0.04±0.01 0.04±0.01 0.7724 0.04±0.01 0.04±0.01 0.6714 0.03±0.01 0.05±0.003 0.0060b)
max AUClast (g∙min/dL) 4.91±2.36 5.26±2.17 0.5634 4.93±2.37 5.52±1.61 0.5964 4.35±1.92 7.67±1.41 0.0061b)
 K01 (1/min) 0.26±0.07 0.24±0.02 0.6801 0.26±0.07 0.24±0.02 0.9578 0.26±0.07 0.23±0.01 0.0182c)
01 KM (g/dL) 3.74±0.31 3.79±0.05 0.6801 3.75±0.28 3.78±0.02 0.711 3.75±0.29 3.80±0.04 0.5708
 VM (1/min) 1.15±0.13 1.17±0.06 0.4579 1.15±0.12 1.16±0.09 0.9578 1.17±0.12 1.10±0.03 0.2568
 Elimination rate (g/L/hr) 0.06±0.03 0.07±0.02 0.4831 0.06±0.03 0.07±0.02 0.4585 0.06±0.02 0.09±0.01 0.0061b)
Blood
 Tmax (min) 38.57±14.06 35.00±12.25 0.5829 37.06±13.12 40.00±17.32 0.7245 39.38±14.36 30.00±0 0.2083
 Cmax (g/dL) 0.03±0.01 0.04±0.01 0.5087 0.03±0.01 0.03±0.01 0.791 0.03±0.01 0.05±0.004 0.0093b)
 AUClast (g∙min/dL) 4.98±2.27 5.35±2.78 0.7415 5.16±2.48 4.69±1.95 0.7913 4.48±2.19 7.52±1.26 0.0182c)
 K01 (1/min) 0.24±0.13 0.23±0.03 0.4095 0.24±0.12 0.25±0.02 0.9578 0.26±0.11 0.18±0.12 0.1859
 KM (g/dL) 3.67±0.60 3.80±0.07 0.8046 3.69±0.54 3.82±0.10 0.711 3.68±0.56 3.84±0.05 0.3447
 VM (1/min) 1.31±0.36 1.23±0.17 0.8046 1.31±0.33 1.15±0.11 0.3683 1.24±0.18 1.45±0.63 0.7768
 Elimination rate (g/L/hr) 0.06±0.03 0.06±0.02 0.7415 0.06±0.03 0.06±0.02 0.6338 0.05±0.02 0.09±0.01 0.0182c)

Tmax, times to reach Cmax; Cmax, maximum concentrations; AUClast, area under the concentration-time curve; K01, absorption rate constant; KM, Michaelis-Menten constant; VM, maximum elimination rate.

a) Mann-Whitney U test;

b) P<0.01;

c) P<0.05.

TOOLS
Similar articles