Folke Sjöqvist

Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin

The frequency of poor metabolizers of debrisoquin was low and similar in four different native Chinese nationalities. In a total sample of 695 Chinese subjects, only seven (1.01%) had a urinary ratio between debrisoquin and 4‐hydroxydebrisoquin >12.6, which is the antimode between poor metabolizers and extensive metabolizers in white populations. This is significantly lower than the 6.82% found in 1011 white Swedish healthy subjects (p < 0.0001). Admixture analysis indicated the occurrence of two distributions within extensive metabolizers among both Chinese and white subjects. The mean of the distribution of metabolic ratios among Chinese extensive metabolizers was shifted toward higher values compared with Swedish extensive metabolizers (p < 0.01). The frequency of poor metabolizers of S‐mephenytoin was higher in 137 Chinese (14.6%) than in 488 Swedish (3.3%) subjects (p < 0.0001). Our findings imply that drugs metabolized by these two polymorphic hydroxylases should be prescribed in different dosages to Chinese and white subjects.

Increased Plasma Protein Binding of Propranolol and Chlorpromazine Mediated by Disease-Induced Elevations of Plasma α1 Acid Glycoprotein

To assess the importance of disease-induced increases in plasma concentrations of alpha1 acid glycoprotein (an acute-phase plasma protein that binds cationic drugs), we determined binding of propranolol in plasma from 53 patients and 25 healthy volunteers. Binding was increased in 10 patients with Crohns disease (P less than 0.002), nine with inflammatory arthritis (P less than 0.002) and eight with chronic renal failure with superimposed inflammatory disease (P less than 0.01) as compared with healthy controls. The plasma binding of control subjects did not differ from that of 12 patients with chronic hepatic disease (P greater than 0.45) or 14 with uncomplicated renal failure (P greater than 0.80). Chlorpromazine binding, determined in 60 subjects, yielded similar results. Percentage of free drug and alpha1 acid glycoprotein concentration were inversely correlated (r = -0.77 with propranolol, P less than 0.001, and r = -0.69 with chlorpromazine, P less than 0.001). Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in alpha1 acid glycoprotein concentration, which may influence drug kinetics.

Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine

The authors describe a 33-year-old woman who experienced severe pain in the epigastrium after codeine intake. This side-effect is consistent with that of morphine. Later, the patient was phenotyped and genotyped as an ultrarapid metabolizer with high capacity to metabolize codeine to morphine.

Determination of bioavailability of diazepam in various formulations from steady state plasma concentration data

The plasma concentrations of diazepam (Valium, Roche Labs., Nutley, N. J.) and its maior metabolite, N‐desmethyldiazepam, after treatment with 5 mg. oral doses three times a day were investigated in 7 subfects. There was a twofold variation in the steady‐state concentrations between subiects. The plasma half‐lifes of diazepam varied between 26 and 53 hours. A crossover study with an evaluation of the bioavailability of 3 manufacturers tablet products and a suspension of diazepam was included in the investigation. The tablets gave similar intraindividual plasma levels while the suspension showed lower values during steady state, thereby indicating incomplete absorption.

Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects.

The CYP2D6 genotype and the debrisoquine and mephenytoin hydroxylation phenotypes were studied in 63 Oriental subjects including 21 Chinese, 21 Japanese and 21 Koreans. All subjects were extensive metabolizers of debrisoquine. The incidence of the S-mephenytoin poor metabolizer phenotype was 14% in the Chinese, 24% in the Japanese and 24% in the Korean population, respectively, which is similar to previous reports. The CYP2D6 genotype was analysed by Xba I and Eco RI RFLP, and by allele-specific PCR analysis for the presence of several allelic variants of the CYP2D locus. No CYP2D6A or CYP2D6B alleles, two of the most common defect alleles among Caucasians, were found among the Oriental subjects. The frequency of the CYP2D6D allele was similar to that in Caucasian populations and consistent with the low incidence of the poor metabolizer phenotype in all three Oriental populations. The CYP2D6L2-allele with duplication of an active CYP2D6L gene was identified in one Korean and one Chinese allele in association with high CYP2D6 activity. The CYP2D6Ch alleles CYP2D6Ch1 and Ch2, identified by RFLP and PCR for the -1338C-->T and 188C-->T mutations, were the most frequent allelic variants in all three populations studied, and were related to a decreased CYP2D6 activity as previously shown in Chinese. In conclusion, the present pilot study revealed major similarities in the polymorphic CYP2D locus between Korean, Japanese and Chinese populations.

The anti-doping hot-line, a means to capture the abuse of doping agents in the Swedish society and a new service function in clinical pharmacology

With the support of the Swedish National Institute of Health a national information service was started in 1993 aiming to capture the abuse of doping agents in the general public. It was organized as a telephone service, called the Anti-Doping Hot-Line, from our department and managed by trained nurses co-operating with clinical pharmacologists. Important information collected about all callers (anonymous) was: date of call, its origin, category of caller, doping experience and main question being asked. Abusers were asked about their age, sex, affiliation, abused drug(s), duration of abuse, habit of administration and adverse reactions (ADRs). Between October 1993 and December 2000 25,835 calls were received with a peak during spring and autumn. Most calls (12,400) came from non-abusers, 60% being males. Callers connected with gyms represented the largest group (30%). Most calls about specific drugs concerned anabolic androgenic steroids (AAS). Other drugs or products included ephedrine, clenbuterol and creatine. The most commonly abused anabolic steroids were testosterone, nandrolone-decanoate, methandienone and stanozolol. The ten most commonly reported ADRs of AAS were aggressiveness (835), depression (829), acne (770), gynecomastia (637), anxiousness (637), potency problems (413), testicular atrophy (404), sleep disorders (328), fluid retention (318) and mood disturbances (302). Female side effects included menstruation disturbances, hair growth in the face, lower voice and enlarged clitoris. During the period 1996–200, totally 4339 persons reported about 10,800 side effects. This figure should be compared with the very low number of ADRs (27) reported by prescribers to the Swedish ADR committee during the same period. Abuse of doping agents appears to be a new public health problem that needs detection, medical care and prevention.

Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia.

The metabolism of many neuroleptics cosegregates catalyzed by the polymorphic cytochrome P450 CYP2D6. The population can be phenotyped into extensive metabolizers (EM) and poor metabolizers (PM) with respect to this enzymes activity. PM are likely to achieve higher than average concentrations of neuroleptic drugs in plasma, with an increased risk of extrapyramidal side effects, possibly including tardive dyskinesia. Sixteen white schizophrenic patients who had developed tardive dyskinesia during long-term neuroleptic treatment were phenotyped with debrisoquine and genotyped by CYP2D6-specific DNA amplification and EcoRI restriction fragment length polymorphism analysis. Only 1 (6%) of the 16 patients had a PM genotype, 8 (50%) were homozygous, and 7 (44%) were heterozygous EM. None had a CYP2D6 genotype indicative of ultrarapid debrisoquine hydroxylation capacity. The patients were also phenotyped with mephenytoin, a probe drug for another polymorphic cytochrome P450, CYP2C19. One patient was a PM of S-mephenytoin, which corresponds to the frequency found in healthy white volunteers. In conclusion, there was no overrepresentation of PM of debrisoquine or of S-mephenytoin among the 16 patients with neuroleptic-induced tardive dyskinesia. However, the PM of debrisoquine had the highest score on the Simpson-Angus Rating Scale and the second highest on the Abnormal Involuntary Movement Scale, despite a very low neuroleptic dose. Also, the debrisoquine MR correlated significantly with the SARS score (rs = 0.685, p < 0.05, N = 10), indicating a relationship between the degree of impaired CYP2D5 activity and the severity of extrapyramidal side effects during neuroleptic treatment.

Enantioselective analysis of chloroquine and desethylchloroquine after oral administration of racemic chloroquine.

Summary: An enantioselective high-performance liquid chromatographic method for chloroquine and desethylchloroquine was developed using a chiral α1-acid glycoprotein column. This method was used to determine concentrations of chloroquine and desethylchloroquine enantiomers in plasma and urine from volunteers given single oral doses of racemic chloroquine. The disposition of the enantiomers was different. The renal clearance of the chloroquine enantiomers was indicative of stereoselective renal secretion of the drug, and evidence for stereoselective metabolism also was found.

A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man.

The steady‐state plasma levels of desmethylimipramine and nortriptyline were compared with the half‐life of oxyphenylbutazone in 5 psychiatric patients, previously treated with various psychotropic drugs. The data showed large interindividual differences, but individuals who achieved a relatively high (or low) steady‐state plasma level (a long or short half‐life) with one drug, also achieved a high (or low) steady‐state plasma level (a long or short half‐life) with the other drugs tested. The findings suggest nonspecificity of the drug hydroxylating enzymes in man. Simultaneous administration of desmethylimipramine did not affect the half‐life of oxyphenylbutazone.

Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics

A short review of the metabolism of psychoactive drugs and the pharmacogenetic factors regulating the enzymes involved is presented here. The potential clinical usefulness of phenotyping and genotyping individuals, with regard to their drug metabolic capacity, is discussed. Indications for genotyping CYP2D6 and a flow scheme for the combined use of conventional therapeutic drug monitoring (TDM) and pharmacogenetic methods for optimizing dosage-schedules of psychoactive drugs are suggested.