Effects of Fasting and Chronic Alcohol Consumption on the First-Pass Metabolism of Ethanol

Transcription

1 GASTROENTEROLOGY 1987;9: Effets of Fasting and Chroni Alohol Consumption on the First-Pass Metabolism of Ethanol CARLO DIPADOV A, THERESA M. WORNER, RISTO J. K. JULKUNEN, and CHARLES S. LIEBER Alohol Researh and Treatment Center, Bronx Veterans Administration Medial Center and Department of Mediine, Mt. Sinai Shool of Mediine (CUNY), Ne York, Ne York The present investigation as undertaken to evaluate hat fration of alohol ingested in amounts during usual "soial drinking" does not enter the systemi irulation. To that effet, on onseutive days, either peroral or intravenous ethanol as administered in both fed and fasted states to 7 nonaloholi and 18 aloholi subjets. In nonaloholis onsuming.15 g/kg body t ethanol, the magnitude of first-pass metabolism of ethanol as 3.94 ±.15 mmo1il. h, alulated as the differene of the areas under the urve obtained after oral and intravenous alohol administration. The first-pass metabolism aounted for 73% of the latter. When the administered dose as inreased to.3 g/kg body t ethanol, the orresponding values ere 6.46 ±.5 mmo1il. hand 44%. Fasting dereased this effet. When aloholis onsumed.15 g/kg body t ethanol, the orresponding values ere.9 ±.65 mmo1il. hand 3%. When these aloholis ere fasted, the first-pass metabolism again dereased and it as signifiantly loer than in the nonaloholis tested under the sa,me onditions. We onlude that in humans a signifiant fration of ingested alohol undergoes first-pass metabolism but that this effet is redued in aloholis and by fasting. The magnitude of this proess determines the bioavailability of alohol and thus modulates its potential toxiity. Reeived August 8, Aepted November 1, Address requests for reprints to: Dr. Charles S. Lieber, M.D., Alohol Researh and Treatment Center, Bronx Veterans Administration Medial Center, 13 West Kingsbridge Road, Bronx, Ne York This ork as supported by grant AA-358 from the Department of Health and Human Servies and by the Veterans Administration. The authors thank J. Saeli and 1. Tannenbaum for expert tehnial assistane and P. Walker for typing the manusript by the Amerian Gastroenterologial Assoiation /87/$3.5 Metabolism of ethanol inthe digestive trat of the rat has been previously reported to exist (1,) and has been related to the alohol dehydrogenase present in this tissue (3,4). Hoever, the magnitude of this metabolism as assumed to be small (1,). Some authors (5) ould not demonstrate any signifiant gastrointestinal ethanol oxidation hen they gave an aute high dose to rats and onluded that this proess as of negligible quantitative signifiane. Reently, e have reopened the issue by shoing that an appreiable fration of alohol ingested in doses in keeping ith usual soial drinking does not enter the systemi irulation in the rat and is oxidized mainly in the stomah (6,7). We proposed that the magnitude of this loal oxidation may modulate the bioavailability of alohol and thus its potential toxiity; e no extend these observations to humans. Materials and Methods Seven male nonaloholis (age 33 ± yr, mean ± SEM) and 18 aloholis (age 4 ± 11 yr) gave signed informed onsent for this investigation, hih as approved by the Human Studies Committee of the Bronx Veterans Administration Medial Center. The aloholis, all of hom reported onsuming in exess of 1 g/day of ethanol for a minimum of 4 mo, ere admitted for detoxifiation. Blood as obtained upon admission for the determination of onventional liver funtion tests. Eight of the 18 aloholis underent liver biopsy. On onseutive days, subjets reeived.15 or.3 glkg body t of ethanol either perorally or intravenously. All patients ere initially studied ithin 48 h of the essation of alohol onsumption. The subjets ere evaluated in both the fasting and fed states. Nonaloholis ere randomly assigned to the fed or fasting state. No order effet as observed hen fasted or fed. For pratial reasons, alo- Abbreviations used in this paper: AUC i. v., area under the urve after intravenous alohol administration; AUC p.o., area under the urve after peroral alohol administration.

2 117 DIP ADOV A ET AL. GASTROENTEROLOGY Vol. 9, No.5, Part 1 7 'f.l 6 : en 5 +1 : ~4 E ~3...J Z «:r: I- Cl g I *.6l -t p<.5 * p<o.oi -- PO. ETHANOL -D.- I. V. ETHANOL ":k' Figure 1. First-pass metabolism of ethanol in 5 nonaloholis after.15 glkg body t ethanol. Ethanol as administered in a 5% dextrose solution (5 g/1 ml) perorally or intravenously 1 h after a standard breakfast. Drinking time as 1 min and that of the intravenous infusion min. The blak area in the figure represents the amount of ingested alohol that did not enter the systemi irulation and expresses the magnitude of the firstpass metabolism of ethanol. Zero blood ethanol levels ere reahed signifiantly earlier after peroral than intravenous ethanol (inset). holies ere tested first in the fasted state and then in the fed state. Breakfast onsisted of to eggs, to slies of baon, to piees of buttered toast, to ups of offee, and 1 ml of orange juie. The infusion rates of ethanol ere seleted to yield peak ethanol onentrations at approximately the same time as the peroral administration. Before and after ethanol administration, heparinized blood samples for the assay of ethanol (8), aetaldehyde (9), and aetate (1) ere olleted through an indelling flexible atheter, inserted into a peripheral vein. The area under the urve as alulated ith the trapezoidal method from the beginning of ethanol administration to the time at hih ethanol as no longer detetable (11). The results are expressed as mean ± SEM. Statistial analysis of the results as performed using the Student's unpaired or paired t-test and nonparametri statistial tehniques suh as the Wiloxon-Mann Whitney test (1). Results As shon in Figure 1, in fed nonaloholi volunteers, muh loer blood ethanol levels ere found after peroral than intravenous ethanol (.15 g/kg body t), indiating that an important fration of the ingested alohol did not enter the systemi irulation. The possibility that this effet as simply related to a delay in ethanol absorption from the gastrointestinal trat as ruled out by the signifiantly earlier disappearane of ethanol from blood after peroral than after intravenous administration (179 ± 7 vs. 4 ± min, p <.5). Moreover, blood levels of the metabolites of ethanol (aetaldehyde and aetate) peaked at similar times and levels after both oral and intravenous alohol administration (Figure ). In the same subjets, the area under the urve after peroral alohol administration (AUCp.oJ as signifiantly loer than the orresponding area under the urve after intravenous alohol administration (AUCLvJ (1.48 ±.19 vs. 5.4 ±.34 mmoll L. h; p <.5). The magnitude of the first-pass metabolism alulated by the differene beteen AUCLv. and AUCp.o. as 3.94 ±.15 mmolll hand it aounted for about 73% of the AUCLv.. When the same nonaloholis reeived.3 g/kg body t ethanol, the orresponding values ere 6.46 ±.5 mmolll hand 44% (Figure 3). These data suggest that, ithin a range of moderate soial drinking, the first-pass metabolism is dose-dependent, but relative to the dose given, it is maximally effetive at a very lo ethanol dosage. When alohol as given in the 3 ~ 1.6 :r: g 1. f:'! ~ J.-- P. O. ETHANOL &---6 I. V. ETHANOL MEAN ~ SEM n W l- f'!.6 u «.4 Cl o g. 3 Figure. Blood aetaldehyde (left) and aetate (right) in 5 nonaloholis after.15 g/kg body t ethanol. Contrasting ith the sloer elevation of blood ethanol levels (Figure 1), the produts of ethanol oxidation (aetaldehyde and aetate) appeared rapidly in the peripheral irulation and at the same time after peroral and intravenous ethanol, suggesting that alohol is oxidized at least as rapidly hen administered perorally.

3 May 1987 FIRST-PASS METABOLISM OF ETHANOL 1171 ~ 1.. ::;; en o i FED t p<o O!5 -- P.Q ETHANOl (O lt/k,) --'.\1 ETHANOL to 39/kll) 1 6 -a-p.o ETHANOL (O 3\1/k\l) -O-I.V ETHANOL(O.3\1/k\l) 8 ';;" 7 ::; (/) 6 +, ::;., 5 it r p<o.o!5 -- P.O ETHANOL (O I!5Q/k",1-6- l.v. ETHANOL {O.15,/kOI Figure 3. Comparison of the first-pass metabolism of ethanol in 3 fed and fasted nonaloholis given.3 g/kg body t ethanol in a dextrose solution (5 g/1 ml). Drinking time as min and that of intravenous infusion 4 min. When alohol as given after the standard morning meal, signifiantly loer blood ethanol onentrations ere found after the peroral than after the intravenous dose. On the other hand, the omparison of the blood ethanol values in the same group of nonaloholis fasted overnight shoed no signifiant differene beteen the ethanol levels after peroral or intravenous administration. ~ ~ 4 -' ~ 3 I f- W -' 1 III 3 Figure 4. First-pass metabolism of ethanol in 7 aloholis after.15 g/kg body t ethanol given perorally or intravenously in the fed state. Alohol as administered as desribed in Figure 1. The first-pass metabolism (represented by the blak area) as signifiantly loer in aloholis, shon here, hen ompared to nonaloholi ontrols (Figure 1). fasting state, there as no signifiant differene in blood ethanol beteen the peroral and the intravenous dose, either for the.15-glkg body t (not shon) or for the.3-glkg body t dose (Figure 3). The differene beteen AUC Lv. and AUC p. a. as redued to.64 ±.5 mmolll. h, a value signifiantly loer (p <.5) than that obtained in the fed state and hih represented only 13% of the AUC Lv. Our results also onfirm the higher systemi levels of ethanol in fasting onditions, ith a greater area under the urve in the fasted than in the fed state (AUC Lv.:.68 ±.76 vs ±.83 mmolll. h, p <.5; AUC p.a.: 18.1 ±.6 vs ±.45 mmolll. h, p <.l). Compared to ontrols, alohous onsuming.15 glkg body t ethanol in the fed state exhibited a loer first-pass metabolism (.9 ±.65 vs ±.15 mmolll h, p <.5) hih aounted for only 3% of the AUC Lv. (Figure 4). When the dose as inreased to.3 glkg body t ethanol, aloholis still had a dereased first-pass metabolism ompared to ontrols (.68 ±.78 vs ±.5 mmolll. h). Fasting dereased the first-pass metabolism in the aloholis. The first-pass metabolism as only 9% of the AUC Lv. in fasted aloholis onsuming.15 g/kg body t ethanol and 6% after.3 g/kg body t ethanol; these values ere signifiantly loer than those obtained in nonaloholis tested under the same onditions (p <.5). Alohol ithdraal resulted in partial orretion of the loss of the first-pass metabolism in aloholis, as shon in Table 1. After only k of ontrolled abstinene, the differene beteen AUC Lv. and AUC p.a. rose from a basal value of.9 ±.65 to.37 ±.13 mmolll. h (p <.5) after.15 g/kg body t ethanol in the fed state. In 1 subjet tested again after 3 k of abstinene, a differene of 3.14 mmolll h as found, hih is similar to that of nonaloholis (3.94 ±.15). In all 8 subjets ho underent biopsy, steatosis as present in variable degrees. One subjet refused liver biopsy. Liver funtion tests at admission for the total group of aloholis ere omparable to the 8 subjets ho underent a diagnosti liver biopsy and ere as follos: albumin, 4.3 ±.1 vs. 4.1 ±. g/dl; aspartate aminotransferase, 9 ± vs. 115 ± 3 U/L; alanine aminotransferase, 6 ± 9 vs. 8 ± 8 U/L; y-glutamyl transpeptidase, 196 ± 46 vs. ± 5 U/L; total bilirubin,.6 ±. vs..6 ±.1 mg/dl; Table 1. Comparison of Areas Under the Curve in Nonaloholis and Aloholis on Admission and After Abstinene a Nonaloholis (n = 5) Aloholis Admission (n = 6) 1 k (n = 1) i< (n = 3) 3 k (n = 1) AUC (mmolll h) 3.94 ±.15.9 ± ± AUC, area under the urve. a With abstinene, there is partial orretion of the loss of first pass metabolism in aloholis.

4 117 DrPADOVA ET AL. GASTROENTEROLOGY Vol. 9, No.5, Part 1 and alkaline phosphatase, 14 ± 9 vs. 114 ± 9 U/L. These moderately abnormal results ere in keeping ith the mild histologi fatty liver hanges. Disussion Our results in humans are onsistent ith previous observations in rats (6) in that a signifiant fration of iiigested alohol does not enter the systemi irulation. Indeed, the administration of equal doses of ethanol, both to aloholis and nonaloholi volunteers, resulted in loer blood ethanol onentrations hen alohol as administered perorally as ompared to the intravenous route. The possibility that this effet as simply related to a delay in ethanol absorption from the gastrointestinal trat as ruled out by the signifiantly earlier disappearane of ethanol from blood after oral than after intravenous administrations. This is onsistent ith our previous observations in rats (6,7), hih demonstrated no signifiant amount of residual alohol in the stomah and small intestine at the time hen blood ethanol onentrations reahed zero values. Moreover, blood levels of the metabolites of ethanol (aetaldehyde and aetate) peaked at similar times and levels after oral and intravenous ethanol (Figure ). This observation provides additional evidene against a delayed metabolism after oral (ompared to intravenous) administration of ethanol. Thus ethanol, like other drugs, undergoes a signifiant firstpass metabolism. Unlike other drugs, hoever, for hih the first-pass metabolism is primarily hepati, in the ase of ethanol our animal studies (6,7) indiate the preponderane of an upper gastrointestinal site. In the nonaloholis, the first-pass metabolism appeared to be dose-dependent ithin the range of "moderate soial drinking": it as maximally effetive at a very lo ethanol dose.(equivalent to one "drink") and as still signifiant at tie that dose. In the aloholis, for a similar alohol dose, a loer first-pass metabolism as observed than in the nonaloholi volunteers. The redued first-pass metabolism in the aloholis may be due, in part, to diminished alohol dehydrogenase ativity, as a signifiant derease of gastri alohol dehydrogenase ativity has been doumented previously by us in rats hronially fed alohol-ontaining diets (6,7) and as alterations in the rate of gastri emptying do not appear to be ontributory (13). In both aloholis and nonaloholis, fasting dereased the first-pass metabolism. In aloholis, hoever, the values ere signifiantly loer than in nonaloholis tested under the same onditions. The loss of the first-pass metabolism in the fasting state has no obvious explanation, but an be tentatively attributed to a ombination of different fators, in partiular to aelerated gastri emptying and inreased intestinal absorption (14,15), hih may redue the presene of alohol in the stomah here its oxidation is maximal (6,7). In addition, hanges in the ativity of both gastri and hepati alohol dehydrogenase may ontribute to the reported effets. Furthermore, it is knon that fasting slos ethanol metabolism (16), probably through the impairment of the reoxidation of the ytosoli niotinamide adenine dinuleotide, redued form, generated by ethanol oxidation via the alohol dehydrogenase pathay (17). Abstinene from alohol resulted in partial orre" tion of the loss of the first-pass metabolism in aloholis after only k. In 1 subjet tested again after 3 k; the first-pass metabolism as similar to that observed in the nonaloholi volunteers. These results suggest a prompt reovery of the alterations in the mehanisms underlying the effet. In this regard, a very rapid restoration of the integrity of the gastri muosa has been reported after ethanol injury in the rat (18,19). We onlude that iii humans, a signifiant fration of alohol ihgested undergoes first-pass metabolism. The magnitude of this proess determines the bioavailability of alohol and thus modulates its potential systemi toxiity. Fasting and prolonged alohol abuse redue the first-pass metabolism, but abstinene for several eeks restores it to the values observed in nonaloholis. Differenes in the apaity of the gastrointestinal trat to metabolize alohol may explain the disrepanies in blood ethanol onentrations that sometimes our in different individuals after ingestion of the same dose of ethanol () depending, among other fators, on onomitant food intake or hroni alohol onsumption, or both. Referenes 1. Lamboeuf Y, De Saint Blanquat G, Derahe R. Muosal alohol dehydrogenase- and aldehyde dehydrogenasemediated ethanol oxidation in the digestive trat of the rat. Biohem PharmaoI1981;3: Lamboeuf Y, La Droitte P, De Saint Blanquat G. The gastrointestinal metabolism of ethanol in the rat. Effet of hroni aldholi intoxiation. Arh Int Pharmaodyn Ther 1983; 61: Cederbaum AI, Pietrusko R, Hempel J, Beker F, Rubin E. Charaterization of a non-hepati alohol dehydrogenase from rat hepatoellular arinoma and stomah. Arh Biohem Biophys 1975;171: Pestalozzi DM, Buhler R, von Wartburg JP, Hess M. Immunohistohemial loalization of alohol dehydrogenase in the human gastrointestinal trat. Gastroenterology 1983;85: Lin GWJ, Lester D. Signifiane of the gastrointestinal trat in the in vivo metabolism of ethanol in the rat. Adv Exp Med BioI 198;13:81-6.

5 May 1987 FIRST-PASS METABOLISM OF ETHANOL Julkunen RJK, Tannenbaum L, Baraona E, Lieber CS. First pass metabolism of ethanol: an important determinant of blood ethanol levels after alohol onsumption. Alohol 1985;3: Julkunen RJK, Di Padova C, Lieber CS. First pass metabolism of ethanol-a gastrointestinal barrier against the systemi toxiity of ethanol. Life Si 1965;37: Korsten MA, Matsuzaki S, Feinman L, Lieber CS. High blood aetaldehyde levels after ethanol administration: differenes beteen aloholi and nonaloholi subjets: N Engl J Med 1975;9: Stoell AR. An improved method for the determination of aetaldehyde in human blood ith minimal ethanol interferene. Clin Chim Ata 1979;98: Guynn RW, Veeh RE. Enzymati determination of aetate. In: Loenstein JM, ed. Methods in enzymology. Ne York: Aademi,1975: Rangno RE, Kreeft JH, Sitar DS. Ethanol 'dose dependent' elimination: Mihaelis-Menten V lassial kineti analysis. Br J Clin PharmaoI1981;1: Snedeor GW, Cohran WG. Statistial methods. 7th ed. Ames, Ioa: Ioa State University Press, 1981: Keshavarian A, Wobbleton J, Greer p, Iber FL. Stomah emptying of solid meal in alohol ithdraal. Alohol Clin Exp Res 1985;9: Welling PG, Tse FLS. Food interations affeting the absorption of analgesi and anti-inflammatory agents. Drug Nutr Interat 1983;: Wilkinson PK, Sedman AI. Sakmar E, Lin YJ, Wagner JG. Fasting and nonfasting blood ethanol onentrations folloing repeated oral administration of ethanol to one adult male subjet. J Pharmaokinet Biopharm 1977;5: Bode JC, Thiele D. Hemmung des Athanolabbaus beim Menshen durh Fasten: Reversibilitat durh Frutoseinfusion. Dtsh Med Wohenshr 1975;1: Meijer AJ, Van Woerkom GM, Williamson JR, Tager JM. Rate-limiting fators in the oxidation of ethanol by isolated rat liver ells. Biohem J 1975;15: Lay ER, Ito S. Rapid epithelial restitution of the rat gastri muosa after ethanol injury. Lab Invest 1984;51: Ito S, Lay ER. Morphology of rat gastri muosal damage, defense, and restitution in the presene of luminal ethanol. Gastroenterology 1985;88:5-6.. Reed TE. Raial omparisons of alohol metabolism: bakground, problems, and results. Alohol Clin Exp Res 1978;:83-7.