Erythrocyte catechol-O-methyltransferase Activity Research Articles

A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat

Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9–1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor

ObjectiveThe present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey. MethodsFour monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity. ResultsOpicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ∼76–84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively. ConclusionsOpicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.

2.244 PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF OPICAPONE, A NOVEL COMT INHIBITOR, DURING FIRST ADMINISTRATION TO HEALTHY MALE SUBJECTS

Aim: Opicapone was developed to fulfill the need for more potent, safer and longer acting catechol-O-methyltransferase (COMT) inhibitors [1]. This study was aimed to assess the tolerability, pharmacodynamics, and pharmacokinetics of single oral doses of opicapone in healthy male subjects. Design: Single rising oral doses of 10mg to 1200mg of opicapone were studied under a double-blind, randomised, placebo-controlled design. Eight sequential groups of 8 subjects were enrolled. Within each group, 6 subjects were randomised to receive opicapone and 2 subjects to receive placebo. Opicapone/placebo was administered after a 10h overnight fasting. Results: The extent and rate of systemic exposure (AUC and Cmax) to opicapone increased in an approximately dose-proportional manner. Despite the relatively short half-life of opicapone (1 to 4h), inhibition of soluble COMT (S-COMT) activity in erythrocytes was long-lasting, ranging from 6% (10mg) to 55% (1200mg) at 72h postdose. Maximum S-COMT inhibition (Emax) occurred between 1 and 6h post-dose (tEmax), and was 34.5%, 71.7%, 93.8%, 96.3%, 100%, 100%, 100% and 100% with the doses of 10, 25, 50, 100, 200, 400, 800 and 1200mg, respectively. Urine levels of opicapone and its metabolites usually remained below the limit of quantification, showing that kidney is not the primary route of excretion. Opicapone was well tolerated at all doses tested. Conclusion: Opicapone was well tolerated at oral single doses of 10mg to 1200mg, presented a dose-proportional kinetics and effectively inhibited erythrocyte soluble COMT activity.

2.245 PHARMACOKINETICS, PHARMACODYNAMICS AND TOLERABILITY OF OPICAPONE, A NOVEL COMT INHIBITOR, DURING MULTIPLE RISING DOSE REGIMENS IN HEALTHY MALE SUBJECTS

Aim: Opicapone was developed to fulfill the need for more potent, safer and longer acting catechol-O-methyltransferase (COMT) inhibitors [1]. This study was aimed to assess the tolerability, pharmacodynamics, and pharmacokinetics of single oral doses of opicapone in healthy male subjects. Design: Single rising oral doses of 10mg to 1200mg of opicapone were studied under a double-blind, randomised, placebo-controlled design. Eight sequential groups of 8 subjects were enrolled. Within each group, 6 subjects were randomised to receive opicapone and 2 subjects to receive placebo. Opicapone/placebo was administered after a 10h overnight fasting. Results: The extent and rate of systemic exposure (AUC and Cmax) to opicapone increased in an approximately dose-proportional manner. Despite the relatively short half-life of opicapone (1 to 4h), inhibition of soluble COMT (S-COMT) activity in erythrocytes was long-lasting, ranging from 6% (10mg) to 55% (1200mg) at 72h postdose. Maximum S-COMT inhibition (Emax) occurred between 1 and 6h post-dose (tEmax), and was 34.5%, 71.7%, 93.8%, 96.3%, 100%, 100%, 100% and 100% with the doses of 10, 25, 50, 100, 200, 400, 800 and 1200mg, respectively. Urine levels of opicapone and its metabolites usually remained below the limit of quantification, showing that kidney is not the primary route of excretion. Opicapone was well tolerated at all doses tested. Conclusion: Opicapone was well tolerated at oral single doses of 10mg to 1200mg, presented a dose-proportional kinetics and effectively inhibited erythrocyte soluble COMT activity.

Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease.

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.

COMT inhibition in the treatment of Parkinson's disease.

A new approach in the treatment of Parkinson's disease is the inhibition of catechol-O-methyltransferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyldopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the Cmax or tmax of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson's disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson's disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.

Ethnic differences in catechol O-methyltransferase pharmacogenetics

Catechol O-methyltransferase (COMT) inactivates neurotransmitters, hormones and drugs such as levodopa. COMT activity is inherited in an autosomal recessive manner and individuals with low activity have thermolabile COMT protein. A low activity allele has been demonstrated at codon 108/158 of the soluble and membrane bound COMT protein, respectively, whereby a G to A transition results in a valine to methionine substitution, rendering the protein more thermolabile. As ethnic differences in erythrocyte COMT activity have been previously demonstrated, the frequency of low activity alleles were investigated in 265 British Caucasian, 99 British South-west Asian and 102 Kenyan individuals. Genotyping of COMT codon 108/158 was performed using a minisequencing method. Erythrocyte COMT activity was measured in 60 British Caucasian individuals by radiochemical assay. The frequency of low activity alleles was 0.54 in Caucasians, 0.49 in South-west Asians, and 0.32 in Kenyans. There was a much lower frequency of individuals with homozygous low activity allele in the Kenyan population (9%) than in Caucasians (31%) or South-west Asians (27%). Erythrocyte COMT activity was lower and less thermostable in individuals with homozygous low activity alleles. The data provide molecular evidence that low COMT is less common in African individuals than the Caucasian population.

No evidence for an association of affective disorders with high- or low-activity allele of catechol- o-methyltransferase gene

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

Validation of assay of catechol- O-methyltransferase activity in human erythrocytes

The multistep assay of specific catechol- O-methyltransferase (COMT) activity in human erythrocytes was validated. Enzyme preparations from lysed erythrocytes were incubated with a substrate (3,4-dihydroxybenzoic acid) in the presence of Mg 2+ and S-adenosylmethionine. The reaction products (vanillic acid and isovanillic acid) were analyzable by HPLC with electrochemical detection directly in the incubation medium after protein precipitation. The precision was calculated in order to define the random variability associated with the method by intra-assay and inter-assay relative standard deviations (RSDs) for the assays of both reaction products and protein. The intra-assay RDSs for the specific activities were between 4.8 and 11.9% ( n = 5−6) at two levels of COMT activity. The inter-assay RSDs were between 6.4 and 14.2% ( n = 5−6), respectively. The total variation was mostly caused by the protein assay and the HPLC assay, and contributions from the sample preparation and incubation steps were minor. Some results from the clinical application of the erythrocyte COMT assay are also reported. For both normal volunteers and patients having Parkinson's disease, a single 400 mg dose of entacapone, a peripherally acting COMT inhibitor, decreased the erythrocyte COMT activity. The application demonstrates that the assay was able to detect differences between the subjects and the effect of COMT inhibition in the clinical study.

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans*

To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Are gender differences genetically related to catecholamine metabolism in schizophrenia?

Serum homovanillic acid (HVA) and norepinephrine (NE), serum dopamine-β-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyltransferase (COMT) have been measured in 86 healthy parents of schizophrenic patients and 36 normal control subjects. The t-test showed that serum HVA concentration was significantly higher in mothers of female patients than in mothers of male patients ( p < .05); Kruskal-Wallis analysis revealed a significant difference in erythrocyte COMT activity among the mothers of male patients, mothers of female patients and female control subjects ( H = 8.7, df = 2, p < .02); and the Mann-Whitney test demonstrated that erythrocyte COMT activity was significantly increased in mothers of male patients as compared with female control subjects ( p < .01), but there were no significant differences in the HVA concentration and COMT activity between the fathers of male and female patients, and male control subjects. There were no significant changes in serum NE concentration, serum DBH and platelet MAO activity in these subjects. The present study suggests that catecholamine metabolism in mothers of schizophrenic patients may play a genetic role in the gender differences of schizophrenia.

Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone.

Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed reversible, tight-binding type of inhibition of soluble rat liver COMT with a Ki-value of 14 nmol/l and it also caused 50% inhibition of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor, since the formation of homovanillic acid (HVA), the O-methyl metabolite of dopamine in the striatum, was not reduced, even after the highest dose of 30 mg/kg. In rat blood serum, the concentration of 3-O-methyldopa (3OMD), the O-methylated product of L-dopa, was reduced in a dose-dependent manner, and the concentration of L-dopa was increased after the administration of entacapone (3-30 mg/kg p.o.) together with L-dopa + carbidopa. These changes were reflected, in the striatum, by a significant rise in the dopamine concentration and a reduction in the 3OMD concentration. Consequently, when entacapone was added to the treatment with L-dopa + carbidopa, the dose of L-dopa could be lowered from 50 mg/kg to 15 mg/kg in order to produce the same striatal dopamine concentrations as with 50 + 50 mg/kg of L-dopa + carbidopa alone.

Effect of a Novel Catechol-O-Methyltransferase Inhibitor, Nitecapone, on the Metabolism of l-Dopa in Healthy Volunteers

A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.

Assignment of the catechol-O-methyltransferase gene to human chromosome 22 in somatic cell hybrids.

Catechol-O-methyltransferase (COMT) plays an important role in the inactivation of catecholamines. It has been demonstrated that erythrocyte COMT activity is genetically determined and controlled by a major autosomal locus with two alleles. The recent development of a method which allows the detection of COMT isozymes directly in autoradiozymograms has provided the means to investigate the chromosome location of the gene by using somatic cell hybrids. We have found that a single form of the COMT enzyme is expressed in several mouse-human fibroblast cell lines. The data obtained from the segregation analysis of the COMT enzyme in these hybrids and their subclones have provided evidence for the location of a major gene for COMT activity on human chromosome 22.

Linkage relationships between a major gene for catechol-o-methyltransferase activity and 25 polymorphic marker systems.

Segregation analysis has provided evidence suggesting the existence of a major gene for catechol-o-methyltransferase (COMT) activity in man. Five large families (4 Caucasian, 1 black), with a total of 1,189 individuals, were ascertained as part of a genetic study of blood pressure. Erythrocyte COMT activity and status at 25 polymorphic genetic marker loci were determined on more than 518 individuals in these pedigrees. Genetic linkage analysis of COMT with each of the 25 marker loci was performed in two ways: 1) using parameter estimates from segregation analysis of untransformed COMT activity, and 2) using parameter estimates from segregation analysis of the power transformation of the COMT activity that maximized the likelihood of the genetic hypothesis in each family. Tight and close linkage were excluded at 21 and 15 loci, respectively. A lod score of 1.27 at theta = 0.1 was found between the loci for COMT activity and phosphogluconate dehydrogenase (PGD). Transformation of the data had little effect on the outcome of the linkage analysis.

Erythrocyte catechol O-methyltransferase activity in schizophrenia: analysis of family data.

The authors determined the erythrocyte catechol O-methyltransferase (COMT) activity of 38 chronic schizophrenic patients, 69 of their first-degree relatives, and 39 normal controls. COMT activity did not distinguish patients from controls. Within families, COMT activity was not associated with schizophrenia spectrum disorders. The data suggest that COMT activity is not an indicator of vulnerability to schizophrenia.

Catechol-O-methyltransferase activity in erythrocytes of persons with severe thermal injury.

In the present investigation, we found that the catechol-O-methyltransferase activity (COMT) in erythrocytes of persons with severe thermal injury was strikingly increased when compared with that in erythrocytes of noninjured individuals. The specific activity of COMT in erythrocytes of burned patients was not correlated with extent of burn. Thus the echinocytes of burned persons are another example of abnormal red cells in which COMT activity is increased. This appears to be the first example of increased COMT activity in abnormal erythrocytes that is not associated with large numbers of reticulocytes.

Catechol-O-methyltransferase activity in erythrocytes of pregnant women with sickle cell disease before, during, and after transfusion and partial exchange transfusion

In the present investigation, we found that the catechol-O-methyltransferase (COMT) activity in erythrocytes of pregnant women with sickle cell disease was strikingly elevated compared with that in erythrocytes of men and pregnant and nonpregnant women. Moreover, the enzyme activity in erythrocytes remained high during and after transfusion or partial exchange transfusion even though the enzyme activity in donor cells was low. This finding is suggestive of the possibility that a factor(s) in plasma of persons with sickle cell disease activates erythrocyte COMT activity.

Assay of Human Erythrocyte Catechol-&lt;i&gt;o&lt;/i&gt;-Methyltransferase Activity with Naturally Occurring Catecholamines as Substrates

This report describes a simple and sensitive radiometric assay for catechol-o-methyltransferase activity in human erythrocytes and other tissues. Saturating concentrations of the endogenous catecholamines and S-adenosylmethionine are used under optimum assay conditions. Erythrocyte catechol-o-methyltransferase activity is also dependent on storage conditions, as activity was lost at -20 degrees C but not at -80 degrees C.

Erythrocyte catechol-O-methyltransferase activity in a Swedish population.

Erythrocyte catechol-O-methyltransferase (COMT) activity has been analyzed in 185 individuals. The activities showed a trimodal frequency distribution. This suggests an autosomal codominant inheritance of the human erythrocyte COMT activity. The mean male COMT activity was 18.9 +/- 7.0 (S.D.) nmol/ml RBC/h. The mean female activity was 16.1 +/- 6.3 nmol/ml RBC/h and the frequency distribution pattern for women was shifted towards lower values.