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O Pelkonen

Publications and source records attributed to O Pelkonen.

At least 19 recordsLinked to original sources
PubMed2005

Human placenta: a human organ for developmental toxicology research and biomonitoring.

Pregnant mothers are exposed to a wide variety of foreign chemicals. This exposure is most commonly due to maternal medication, lifestyle factors, such as smoking, drug abuse, and alcohol consumption, or occupational and environmental sources. Foreign compounds may interfere with placental functions at many levels e.g. signaling, production and release of hormones and enzymes, transport of nutrients and waste products, implantation, cellular growth and maturation, and finally, at the terminal phase of placental life, i.e. delivery. Placental responses may also be due to pharmaco-/toxicodynamic responses to foreign chemicals, e.g. hypoxia. On the other hand, placental xenobiotic-metabolizing enzymes can detoxify or activate foreign chemicals, and transporters either enhance or prevent cellular accumulation and transfer across the placenta. The understanding of what xenobiotics do to the placenta and what the placenta does to the xenobiotics should provide the basis for the use of placenta as a tool to investigate and predict some aspects of developmental toxicity. This review aims to give an update of the fate and behavior of xenobiotics in the placenta from the viewpoint of xenobiotic-metabolizing enzymes and transporters. Their response levels will be described according to gestational status and methods used. The effects of foreign chemicals on placental metabolizing enzymes will be discussed. Also, interactions in the transporter protein level will be covered. The role of the placenta in contributing to developmental effects and fetotoxicity will be examined. The toxicological effects of maternal medications, smoking, and environmental exposures (dioxins, pesticides) as well as some possibilities for biomonitoring will be highlighted.

Animals↗
PubMed2004

Cerebral CT and MRI findings in cervicocephalic artery dissection.

PURPOSE: To explore the frequency and patterns of brain infarction and other brain manifestations in cervicocephalic artery dissection (CCAD) and to evaluate the correlation between vessel wall findings and infarctions. MATERIAL AND METHODS: The medical records and films of 136 consecutive CCAD patients diagnosed in Oulu University Hospital during the 20-year period since 1982 were reviewed. Five patients with no brain imaging were excluded. RESULTS: One-hundred-and-twenty-seven patients underwent cerebral CT and four patients MRI. Brain infarction was detected in 73 patients (56%), 43 of whom had cerebral infarction associated with anterior circulation dissection and 30 cerebellar infarction associated with posterior circulation dissection. Occlusion of the dissected vessel was accompanied by infarction in 76%, irregular stenosis in 40%, and other findings in 12%. Of the anterior circulation infarctions, territorial and subcortical infarctions and territorial infarctions with fragmentation, which are considered embolic, accounted for 95%, while only 5% were in the watershed area and considered hemodynamic. Intracranial posterior circulation dissection rarely caused infarction (in 1/11 of the dissected vessels), whereas intracranial anterior circulation dissection resulted in infarction more commonly (9/12). Altogether 23% of patients with intracranial CCAD had subarachnoid hemorrhage. Hemorrhagic transformation was present in five patients. CONCLUSIONS: More than half of CCAD patients have cerebral or cerebellar infarction at CT or conventional MR imaging. Occlusion of the dissected vessel is accompanied by infarction more often than other vessel wall abnormalities. Most cerebral infarctions caused by arterial dissections are of embolic origin. Intracranial dissections cause subarachnoid hemorrhage in more than 20% of patients.

Adolescent↗
PubMed2004

Diabetic retinopathy: sonographically measured hemodynamic alterations in ocular, carotid, and vertebral arteries.

PURPOSE: To compare local ophthalmic blood flow changes with flow changes in carotid and vertebral arteries in diabetic patients with retinopathy of different grades. MATERIAL AND METHODS: Ten patients with proliferative or preproliferative retinopathy, 10 with mild retinopathy, and 10 matched controls were prospectively studied with ultrasound. Color and duplex Doppler imaging was used to quantitate blood flow in the central retinal arteries (CRA), ophthalmic arteries (OA), common carotid (CCA) and vertebral arteries (VA). Peak systolic velocity (PSV), mean velocity (MV), and resistance index (RI) in CRA, OA, CCA and VA, and volume flow (VF) were measured in CCA and VA. RESULTS: There was a non-significant increase in the CRA and OA velocities in mild retinopathies, a decrease of about 30% in MV, and a slightly increased RI in proliferative or preproliferative retinopathies. There was a decrease of about 15% in the carotid MV and a 20% decrease in the vertebral MV and a decrease of about 30% in VF in the CCA and VA in severe retinopathies. The MV ratio of CRA/CCA was lower in the severe retinopathy group than in the controls. CONCLUSION: The study showed a non-significant increase of ocular blood flow velocities in mild diabetic retinopathy and a significant decrease of flow velocities in severe diabetic retinopathy. This decrease in flow primarily seems to reflect the general decrease of blood flow in the cervical arteries.

Aged↗
PubMed2003

Extracranial internal carotid and vertebral artery dissections: angiographic spectrum, course and prognosis.

We reviewed the clinical and radiological findings of 93 consecutive patients with 111 extracranial internal carotid (ICAD) and vertebral artery (VAD) dissections and one concomitant intracranial VAD; 83% of the patients had unilateral and 17% multiple vessel dissections. The diagnosis was made by intra-arterial digital subtraction angiography in 92 patients and MR angiography in one. Follow-up angiography was performed in 77 cases (83%): of 49 initially stenotic arteries, 40 became completely or almost completely normal, while three showed slight improvement. Of 30 initially occluded arteries, nine had completely or partly recanalised. Of 12 pseudoaneurysms eight were unchanged at follow-up. The proximal vertebral artery was involved as often as the C1-C2 level. Recurrences were rare: a new dissection in another vessel was found in three patients. Kinking or coiling was found in 23% of the dissected internal carotid arteries.

Adolescent↗
PubMed2003

Cardiac arrest after interscalene brachial plexus block with ropivacaine and lidocaine.

Serious adverse reactions to ropivacaine and lidocaine are rare. In this report, we describe a case of sudden cardiac arrest after an interscalene brachial plexus block with a mixture of 150 mg of ropivacaine and 360 mg of lidocaine in a previously healthy, 34-year-old, 97-kg man. Severe hypotension occurred after successful resuscitation, necessitating an infusion of epinephrine. The patient developed pulmonary oedema, and was mechanically ventilated for 22 h. He eventually made a good recovery. We conclude that although ropivacaine and lidocaine are often considered relatively safe local anesthetics, serious cardiovascular complications can occur after the use of these drugs.

Adult↗
PubMed2003

Associations of blood pressure with carotid intima-media thickness in elderly Finns with diabetes mellitus or impaired glucose tolerance.

The aim of the present study was to evaluate the associations of ultrasonographic manifestations of carotid atherosclerosis with systolic (SBP) and diastolic blood pressure (DBP) and pulse pressure (PP) in 65-year-old Finns drawn from a population-based cohort. Carotid ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance (IGT) and 57 normoglycaemic subjects (NGT). The subjects were classified into four quartiles of SBP, DBP and PP. SBP, DBP, PP and the use of antihypertensive drugs increased along with the deterioration of glucose status. The maximal intima-media thickness (IMT) of the common carotid artery (CCA) from the lowest to the highest quartiles of SBP was 0.98+/-0.34, 1.00+/-0.35, 1.03+/-0.29, 1.18+/- 0.52 mm (P=0.038), respectively. SBP was higher (161+/-22 mmHg) in the subjects with severe intima-media thickening (maximal IMT CCA > or =1.2 mm) than in those with maximal IMT CCA of <1.2 mm (153+/- 20 mmHg) (P=0.030). DBP and PP tended to be higher in the former than the latter group (DBP: 89+/-9 mmHg vs 86+/-9 mmHg, P=0.055 and PP: 72+/-18 mmHg vs 67+/-17 mmHg, P=0.159). The prevalence of severe intima-media thickening was 39% in the subjects in the highest SBP quartile (> or =170 mmHg) and 20% in the subjects with lower SBP (P=0.008). In multiple regression analysis, the adjusted OR for severe intima-media thickening was 2.9 (95% CI 1.1-7.9) in the subjects in the highest SBP quartile compared to the subjects with lower SBP. In the present study, high SBP was associated with severe carotid intima-media thickening. We suggest that the results can be generalized to apply to elderly Finnish subjects with DM and IGT, but not to normoglycaemic subjects, on the basis of this study.

Aged↗
PubMed2001

cAMP mediated upregulation of CYP2A5 in mouse hepatocytes.

CYP2A5 is induced by a large number of chemicals including some cAMP modifiers. In a primary hepatocyte model, stimulation of the cAMP signal transduction pathway by glucagon and isoproterenol, acting via specific G-protein coupled plasma membrane receptors, produced up to 17-fold increases in the marker activity of CYP2A5, coumarin 7-hydroxylase. In contrast, glucagon and isoproterenol caused no significant effects on two other major CYP forms, CYP2B10 and CYP1A1/2. Phenobarbital (PB) elicited a 3-fold increase in CYP2A5 expression (catalytic activity and mRNA), while the cAMP and protein kinase A (PKA) stimulators dibutyryl-cAMP, forskolin and Sp-cAMPs caused up to 18-fold increases in the amount of CYP2A5 mRNA. Coadministration of PB and cAMP/PKA stimulating agents produced an additive inducing effect. The expression of CYP2A5, but not CYP2B10 or CYP1A1/2, in DBA/2 mice displayed a marked circadian rhythm, the level of expression being highest in the evening. These results suggest that among xenobiotic metabolizing CYP enzymes, CYP2A5 is uniquely upregulated by cAMP, possibly having the physiological function of priming the olfactory and digestive systems for nocturnal feeding.

Animals↗
PubMed2001

In vitro prediction of gastrointestinal absorption and bioavailability: an experts' meeting report.

The most convenient route of drug administration is peroral. To reach their target, drug molecules must be absorbed from the gastrointestinal tract and enter the systemic circulation in sufficient quantities. For this reason, understanding and anticipating the mechanisms and factors affecting gastrointestinal absorption and metabolism are of the utmost importance in developing new drugs. In contrast to drugs, which are administered intentionally for therapeutic reasons, chemical residues in food and other matrices enter the body unintentionally. Hence, in this case, a low systemic availability would be advantageous. For many reasons, but particularly because of financial and ethical (reduced used of animals) considerations, in vitro and ex vivo approaches to this problem have been pursued over the last few years. The use of in vitro methods, however, inherently creates questions about the validity of extrapolation to the in vivo situation. The purpose of this report is to review the current status of the field and to identify major gaps in our knowledge. Currently, there are a number of in silico, in vitro, cultured cell-based and ex vivo approaches available to predict the cell permeation, absorption and gastrointestinal metabolism of molecules. Some strengths and weaknesses of these approaches are presented, together with a discussion of genetic, environmental, physiological and pathological factors responsible for interspecies and inter-individual variability in these processes. Recent advances in our understanding of active processes such as gut epithelial transporters, involved in absorption, and drug-metabolising enzymes, responsible for intestinal presystemic metabolism, are highlighted. Some major research priorities are identified, including the need for high-quality, information-rich databases against which testing methods being developed can be prevalidated and validated. Preclinical drug development is changing rapidly, and the role of in vitro and ex vivo approaches in this process is becoming increasingly more important. Methods available now are very useful in the drug discovery and development process, including lead compound selection and optimisation and in the design of very early clinical studies, but whether any of them will eventually obviate the need for clinical trials of bioavailability is still very debatable and will require their full validation. It is clear, however, that the results from such in vitro tests are important in shaping drug discovery and the early preclinical drug development process. For other environmental, industrial and household chemicals to which humans are exposed, in particular new chemicals, results from in vitro studies might be the only source of information concerning systemic availability.

Animals↗
PubMed2001

Distribution of cytochrome P4501A (CYP1A) in the tissues of Baltic ringed and grey seals.

Information about the expression of CYP1A in wildlife species is essential for understanding the impact of organochlorine exposure on the health status of an exposed population. Therefore, we aimed at characterising a putative CYP1A enzyme expression in both hepatic and extrahepatic tissues of ringed and grey seals from the Baltic Sea and from less polluted waters. The cellular localisation of CYP1A was identified using a monoclonal antibody against scup P4501A1 (MAb 1-12-3). Immunohistochemical staining showed the highest level of CYP1A expression in liver hepatocytes, and the second highest level in the endothelial cells of capillaries and larger blood vessels in the liver and other organs. The most frequent and strongest staining was found in Baltic ringed seals. Although CYP1A-positive staining was observed in only a few tissues in the other seal populations, it was more intense in Baltic grey seals than in Canadian grey seals. The CYP1A enzyme activity, expressed as ethoxyresorufin O-deethylation (EROD), followed a similar tissue distribution and geographical pattern as the immunohistochemistry with clearly elevated EROD activities in most tissues of both Baltic seal populations. Immunochemical characterisation by immunoblotting confirmed the presence and elevation pattern of a putative CYP1A protein in ringed and grey seals, supporting our findings using other methods. The evenly distributed elevation of CYP1A expression among most of the tissues examined indicates that Baltic seals are exposed to CYP1A inducing agents affecting the whole body. This may result in an increased or decreased toxic potential of foreign substances, which may ultimately determine the biological effects of the contaminants.

Animals↗
PubMed2001

Characterization of xenobiotic-metabolizing cytochrome P450 (CYP) forms in ringed and grey seals from the Baltic Sea and reference sites.

Earlier studies have shown that members of the cytochrome P4501 (CYP1) enzyme family are constitutively expressed, and are elevated in the livers of ringed seals (Phoca hispida) and grey seals (Halichoerus grypus) living in the heavily polluted Baltic Sea. In this study, we compared the expression profiles of several additional CYP enzymes in the liver and extrahepatic tissues of Baltic ringed and grey seals with the corresponding CYP expression in seals from relatively unpolluted waters. We used marker enzyme activity levels, diagnostic inhibitors and immunoblot analysis to assess members of the CYP2A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A sub-families. Coumarin 7-hydroxylation (COH), a marker of CYP2A activity, was high in the liver and the lungs of all the studied seal populations. The presence of a putative CYP2A form in these seals was further supported by the strong inhibition of COH activity by a chemical inhibitor and by an anti-CYP2A5 antibody. However, antibodies to human and rodent CYP2B, CYP2C and CYP2E forms did not recognize any proteins in these seal species. Dextromethorphan O-demethylation (marker for CYP2D activity) and chlorzoxazone 6-hydroxylation (marker for CYP2E activity) were measurable in the livers of all the seals we studied. Both activities were elevated in the Baltic seal populations, showed a strong positive correlation with CYP1A activity and were at least partly inhibited by a typical CYP1A inhibitor, alpha-naphthoflavone. Further studies are needed to determine the presence and characteristics of CYP2D and CYP2E enzymes in ringed and grey seals. Testosterone 6beta-hydroxylation, a CYP3A marker, showed a relatively high level of activity in the livers of both seal species and was potently inhibited by ketoconazole, a CYP3A-selective inhibitor. The putative CYP3A activity showed an opposing geographical trend to that of CYP2D and CYP2E, since it was elevated in the control area. CYP3A protein levels, revealed by immunoblotting, showed a positive correlation with testosterone 6beta-hydroxylation. We conclude tentatively that CYP2A- and CYP3A-like enzymes are expressed in ringed and grey seals, but that CYP2B- and CYP2C-like ones are not. Further information on the individual contaminant profile is needed before any conclusions can be drawn on a possible connection between the varying CYP expressions and the contaminant load.

Animals↗
PubMed2001

The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue.

Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYPIAI mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5. and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs. responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites. are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.

Adult↗
PubMed2001

Polymorphisms of CYP2A6 and its practical consequences.

CYP2A6 is an hepatic enzyme predominantly with some expression in specialized extrahepatic cell types. The CYP2A6 enzyme has a somewhat restricted active site, accepting only a few xenobiotics as substrates. Interest in CYP2A6 has risen considerably after nicotine and some tobacco specific nitrosamines were established as high-affinity substrates for this enzyme. Recently, the organization and structures of the CYP2A gene cluster and several polymorphic alleles of the CYP2A6 gene have been characterized. Two alleles with a point mutation and at least three different types of gene deletion, all leading to deficient gene function, have been found. The frequencies of these alleles vary considerably among different ethnic populations, the deletion alleles being most common in Orientals (up to 20%). The frequency of point mutations are low in all populations studied thus far (< 3%). Several case-control studies have addressed the relationship between CYP2A6 status and smoking habits as well as the role of CYP2A6 polymorphism in lung cancer risk. Studies in Japanese suggest that CYP2A6 poor metabolizer genotypes result in altered nicotine kinetics and may lower cigarette smoking elicited lung cancer risk, whereas similar studies in Caucasian populations have not revealed any clear associations between variant CYP2A6 genotypes and smoking behaviour or lung cancer predisposition.

Alleles↗
PubMed2001

Carbamazepine: a 'blind' assessment of CVP-associated metabolism and interactions in human liver-derived in vitro systems.

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7-ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liver-derived systems provide useful information for prediction of metabolic routes, rates and interactions.

Anticonvulsants↗
PubMed2001

Cytochrome P450 3A expression in the human fetal liver: evidence that CYP3A5 is expressed in only a limited number of fetal livers.

CYP3A is the major cytochrome P450 subfamily constitutively expressed in the human liver. CYP3A4 is the predominant hepatic P450 form in adults and it is expressed at high but very variable levels among individuals. The fetal liver contains mainly CYP3A7, while the presence of the other CYP3A enzymes in fetal liver has remained controversial. In this study, the relative levels of CYP3A4, CYP3A5 and CYP3A7 expression were determined in a panel of 9-11 fetal livers with a similar gestation age (9-12 weeks) and compared to adult livers. CYP3A7 was found to be the major CYP3A form in all the fetal liver samples. The abundance of CYP3A7 varied more at the mRNA (77-fold variation) than at the protein level (4.8-fold variation). CYP3A5 mRNA was also detected in all of the fetal liver samples, but the average level was 700-fold lower than that of CYP3A7. CYP3A5 protein was detected by immunoblot analysis in only 1 fetal liver out of the 9 investigated, the level of expression being moderately high in this sample. CYP3A4 mRNA was detected in only a subset of the fetal liver samples and its level was the lowest of the CYP3A forms. This is the first study to demonstrate the polymorphic expression of CYP3A5 and the variability of CYP3A7 expression in fetal liver and suggests that significant interindividual differences in the metabolism of xenobiotics may already exist at the prenatal stage. These differences may contribute to individual pharmacological and/or toxicological responses in the fetus.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene.

Currently, there are no selective, well characterized inhibitors for CYP2A6. Therefore, the effects of trans-(+/-)-2-phenylcyclopropylamine (tranylcypromine), a potent CYP2A6 inhibitor, on human liver microsomal cytochromes P450 (CYP) were studied to elucidate its selectivity. The IC50 value of tranylcypromine in coumarin 7-hydroxylation (CYP2A6 model activity) was 0.42 +/- 0.07 microM and in chlorzoxazone 6-hydroxylation (CYP2E1 model activity) 3.0 +/- 1.1 microM. The IC50 values for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activities were >10 microM. Potency and selectivity of tranylcypromine were strongly dependent on the amine group, because its nonamine analog cyclopropylbenzene was much less potent inhibitor of CYP1A, CYP2A6, CYP2C19, and CYP2E1 activities and did not inhibit at all CYP2C9, CYP2D6, or CYP3A4 activities. In human liver microsomes tranylcypromine induced type II and cyclopropylbenzene type I difference spectrum. According to the double reciprocal analysis of these spectral responses both tranylcypromine and cyclopropylbenzene may have at least two P450-related binding sites in liver microsomes. The K(a) values of tranylcypromine varied from 4.5 to 15.1 microM and -34.3 to 167 microM in microsomes derived from three different livers and of cyclopropylbenzene from -1.6 to 10.1 microM and -34.6 and 75.2 microM in the same liver microsomes. Based on these results, tranylcypromine seems an adequately selective CYP2A6 inhibitor for in vitro use.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

An assessment of human liver-derived in vitro systems to predict the in vivo metabolism and clearance of almokalant.

The ability of various human derived in vitro systems to predict various aspects of the in vivo metabolism and kinetics of almokalant have been investigated in a multicenter collaborative study. Although almokalant has been withdrawn from further clinical development, its metabolic and pharmacokinetic properties have been well characterized. Studies with precision-cut liver slices, primary hepatocyte cultures, and hepatic microsomal fractions fortified with UDP-glucuronic acid all suggested that almokalant is mainly glucuronidated to the stereoisomers M18a and M18b, which is in good agreement with the results in vivo. Both in vivo and in vitro studies indicate that the formation of M18b dominates over that of M18a, although the difference is more pronounced with the in vitro systems. Molecular modeling, cDNA-expressed enzyme analysis, correlation analysis, and inhibition studies did not clearly indicate which P450 enzymes catalyze the oxidative pathways, which may indicate a problem in identifying responsible enzymes for minor metabolic routes by in vitro methods. All of the in vitro systems underpredicted the metabolic clearance of almokalant, which has previously been reported to be a general problem for drugs that are cleared by P450-dependent metabolism. Although few studies on in vivo prediction of primarily glucuronidated drugs have appeared, in vitro models may consistently underpredict in vivo metabolic clearance. We conclude that in vitro systems, which monitor phase II metabolism, would be beneficial for prediction of the in vivo metabolism, although all of the candidate liver-derived systems studied here, within their intrinsic limitations, provided useful information for predicting metabolic routes and rates.

Anti-Arrhythmia Agents↗
PubMed2001

CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes.

In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19.

Antiparkinson Agents↗