Br. J. clin. Pharmac. (1988), 26, 96-99

Effects of H2-receptor antagonists on ethanol metabolism inJapanese volunteers

EINOSUKE TANAKA & 1KOICHI NAKAMURAInstitute of Community Medicine and 'Institute of Clinical Medicine, University of Tsukuba, Tsukuba-shi,Ibaraki-ken 305, Japan

The effects of H2-receptor antagonists (cimetidine, ranitidine, and famotidine) on ethanolmetabolism were investigated. Neither in aldehyde dehydrogenase (ALDH)-1 deficientsubjects nor in those with normal ALDH-1, did the three H2-receptor antagonists andplacebo differ in their effects on the pharmacokinetic parameters of ethanol (i.e. peak time(tmax), metabolic rate (ko), peak serum concentration (Cmax), volume of distribution (V)and area under the concentration-time curve (AUC). The AUC of acetaldehyde wasslightly but significantly (P < 0.05) larger only after treatment with cimetidine. Cmax andtmax of acetaldehyde were unchanged.

Keywords H2-receptor antagonist ethanol acetaldehyde drug interaction

Introduction Methods

Cimetidine, a histamine H2-receptor antagonist,is a competitive inhibitor of the hepatic cyto-chrome P-450 mixed function oxidase system(Somogyi & Gugler, 1982; Somogyi & Muirhead,1987). Ranitidine and famotidine do not inhibitthis system (Cate et al., 1986; Locniskar et al.,1986).Ethanol is probably the most common non-

prescription drug taken regularly with medication.Studies by Harada et al., (1978, 1980) demon-strated a genetic polymorphism in acetaldehydedehydrogenase (ALDH) which is involved in themetabolism of acetaldehyde, the primary meta-bolite of ethanol. They found that individualscan be grouped into those with the ALDH-1isozyme and those without it.

In this study, subjects were grouped into thosewithout ALDH-1 isozyme and those withALDH-1 isozyme and the effects of three H2-receptor antagonists (cimetidine, ranitidine andfamotidine) on the metabolism of ethanol andacetaldehyde were investigated.

Twelve healthy male volunteers consented toparticipate in the study. Six out of these (20-21years in age, and 50-61 kg in weight) were of thenormal ALDH-1 type and the others (20-22 yearsin age, and 55-73 kg in weight) were of theALDH-1 deficient type. The hair root samplingmethod described by Goedde et al. (1983) wasused for this identification. Some of the subjectsconsumed alcohol (up to 10 g/week) and cigar-ettes (up to 10/day). Each subject received oneof the three H2-receptor antagonists (cimetidine200 mg four times daily, ranitidine 150 mg twicedaily, famotidine 20 mg twice daily) or placebo(four times daily) for 1 week before ethanol in-gestion according to a cross-over design. On theday of ethanol ingestion, the subjects took thefinal dose of H2-receptor antagonist or placebobetween 09.00 h and 09.30 h after an overnightfast. Thirty minutes later they ingested ethanolin the form of whisky containing 40% v/v alcoholover 10 min. The dose of ethanol was 0.8 g kg-'for normal ALDH-1 type subjects and 0.4 g kg-'

Correspondence: Dr Einosuke Tanaka, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken305, Japan

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Table 1 Pharmacokinetic parameters (mean ± s.d.) of ethanol in ALDH-1 normaland ALDH-1 deficient subjects with and without treatment with H2-receptorantagonists

Cmax tmax K0 V AUC (0,oo)Treatment (mg ml-') (h) (mg h-1) (1) (mgml-' h)

ALDH-J normal subjectsPlacebo 1.12 ± 0.13 0.67 ± 0.22 0.18 ± 0.02 37.5 ± 1.9 5.17 ± 0.25Cimetidine 1.11 ± 0.16 0.92 ± 0.40 0.18 ± 0.03 38.0 ± 1.1 5.23 ± 0.47Ranitidine 1.10 ± 0.15 0.92 ± 0.30 0.17 ± 0.02 38.5 ± 2.2 5.15 ± 0.35Famotidine 1.14 ± 0.30 0.75 ± 0.34 0.17 ± 0.02 37.7 ± 2.0 5.15 ± 0.70

ALDH-1 deficient subjectsPlacebo 0.62 ± 0.07 0.42 ± 0.20 0.14 ± 0.02 42.1 ± 3.1 2.16 ± 0.16Cimetidine 0.64 ± 0.11 0.46 ± 0.24 0.12 ± 0.01 37.5 ± 3.6 2.50 ± 0.24Ranitidine 0.64 ± 0.12 0.33 ± 0.10 0.13 ± 0.01 40.3 ± 2.3 2.65 ± 0.35Famotidine 0.62 ± 0.09 0.46 ± 0.28 0.14 ± 0.01 40.9 ± 2.9 2.11 ± 0.14

for ALDH-1 deficient subjects. Blood sampleswere collected from the median cubital veinbefore and 15 min, 30 min, and 1, 1.5, 2, 2.5, 3,4, and 6 h after ethanol ingestion. The subjectsremained sitting throughout the period of thestudy. Meals were not taken for 3 h after thebeginning of ethanol ingestion. The individualtrial sessions were separated by an interval of notless than 1 week. Drugs and ethanol were notpermitted for 3 days before and during the periodof treatment. The whole course of the trial con-sisting of four sessions was completed within 3months in each subject. The assays were done byan analyst who was blind to the dosing schedules.Serum ethanol and acetaldehyde concentra-

tions were measured by a modification of themethod of Duritz & Truitt (1964).

Standard curves were constructed with samplesfrom each subject for ethanol (0.12-3.46 mg ml-')and acetaldehyde (0.22-6.6 ,ug ml-l). Thebetween day coefficient of variations (CV) forthe ethanol assay were 5.8% at 0.12 mg ml-'(n = 5) and 1.6% at 3.46 mg ml-' (n = 5); forthe acetaldehyde assay, they were 6.4% at 0.22ug ml-' (n = 5) and 2.6% at 6.6 ,ug ml-1 (n = 5).The peak serum concentrations (Cman) and

the peak times (tm.) of ethanol and acetaldehydewere obtained directly from the serum data. Thezero order elimination rate (Ko) of ethanol wascalculated by linear regression of the terminalserum concentration-time data. The apparentvolume of distribution (V) of ethanol was calcu-lated from the ratio of the administered dose tothe serum concentration extrapolated to timezero. The areas under the curves (AUC) ofethanol (0,oo) and acetaldehyde (0,4 h) werecalculated using the trapezoidal rule.The results are expressed as means ± s.d.

Differences among the four treatment groupswere assessed by the Newman-Keuls test after

repeated measures analysis of(ANOVA).

variance

Results

As shown in Table 1, neither in the ALDH-1deficient subjects nor in those with normalALDH-1 did the three H2-receptor antagonistsand placebo significantly differ from each otherin their effects on the pharmacokinetic para-meters of ethanol.Acetaldehyde data are shown in Table 2.

Although Cmax and tmax did not significantlydiffer between the drug and placebo treatments,AUC values were significantly (P < 0.05) in-creased during cimetidine-treatment.

Discussion

Individuals of the ALDH-1 deficient type aremore frequent amongst Japanese (about 50% ofthe population) than amongst Europeans. Thecause of alcohol induced flushing is thought to bea disturbance of acetaldehyde metabolism owingto a deficiency in ALDH-1, one of the 4 isozymesof ALDH. A polymorphism of ethanol metabo-lism has been reported (Harada et al., 1980).

In the present study, the AUC value of acetal-dehyde in the ALDH-1 deficient individuals wassignificantly (P < 0.05) increased after cimetidinetreatment (Table 2). This suggests that, inALDH-1 deficient individuals, co-administrationof cimetidine and ethanol leads to an inhibitionof acetaldehyde metabolism. An interpretationof this finding is as follows: In ALDH-1 normalindividuals (having a low Km for ALDH activity)acetaldehyde is rapidly metabolized chiefly inthe hepatic mitochondrial fraction. However, in

98 Einosuke Tanaka & Koichi Nakamura

Table 2 Pharmacokinetic parameters (mean ± s.d.) ofacetaldehyde in ALDH-1 normal and ALDH-1 deficientsubjects with and without treatment with H2-receptorantagonists

Cmax tm AUC (0,4)Treatment (ig ml-,) (h) (,ug ml- h)

ALDH-1 normal subjectsPlacebo 0.91 ± 0.24 1.01 ± 0.08 2.04 ± 0.32Cimetidine 0.90 ± 0.33 1.17 ± 0.22 2.07 ± 0.62Ranitidine 0.95 ± 0.42 1.08 ± 0.16 2.04 ± 0.70Famotidine 0.91 ± 0.37 1.08 ± 0.14 2.23 ± 0.64ALDH-1 deficient subjectsPlacebo 2.43 ± 0.39 0.42 ± 0.10 4.61 ± 0.24Cimetidine 2.45 ± 0.15 0.38 ± 0.12 5.00 ± 0.50*Ranitidine 2.38 ± 0.22 0.46 ± 0.08 4.21 ± 0.13Famotidine 2.30 ± 0.35 0.42 ± 0.10 4.21 ± 0.20

* P < 0.05 compared to all other groups (Newman-Keulstest)

ALDH-1 deficient individuals (having high Kmfor ALDH activity) metabolism occurs in thehepatic microsomal and cytosol fractions (Leb-sack et al., 1981). Cimetidine inhibits drugmetabolism by binding to hepatic microsomalcytochrome P-450. Therefore, such inhibitionmay account for a selective effect on acetalde-hyde metabolism in ALDH-1 deficient indi-viduals.According to Feely & Wood (1982), cimetidine

(300 mg x 4/day for 7 days) increased the plasmaconcentrations and AUC values of ethanol inhealthy volunteers. They suggested that thisincrease was due to inhibition of ethanol meta-bolism by cimetidine. Seitz et al. (1983, 1984)also found increased plasma ethanol concentra-tions and AUC values after cimetidine but notafter ranitidine. Tan et al. (1983) speculated thatcimetidine may increase the absorption rate ofethanol by increasing gastric emptying. Dobrillaet al. (1984) treated six healthy volunteers with

cimetidine (400 mg x 2/day) or ranitidine(150 mg x 2/day) for 7 days, and gave ethanolthereafter. No significant change in blood etha-nol concentrations was observed after eithertreatment, and it also suggested that cimetidinedoes not affect ethanol oxidation (Johnson et al.,1984). These discrepancies in the effect of cimeti-dine on ethanol metabolism may be a reflectionof methodological differences. The differencesin the dose of cimetidine might also be a factor.Thus, the dose used by Feely & Wood (1982)was 1.25 times, and that used by Seitz et al.(1983, 1984) was 1.5 times higher than the doseused in the present study. In addition, the type ofethanol beverage and food intake may haveaffected the rate and the extent of ethanol absorp-tion by changing gastric emptying rate.Our results suggest that ranitidine and famo-

tidine at therapeutic doses will not greatly affectethanol metabolism in either normal ALDH-1subjects or in those who are ALDH-1 deficient.

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(Received 9 October 1987,accepted 17 March 1988)