Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.

The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.

The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 2.1 vs 17.2 + 8.0, p < .001), lower average plasma concentration (Cp) (1.1 + 0.6 vs 2.5 ± 0.5 ng/ml/mg daily dosage, p < .001), and higher oral clearance (1115 ± 1238 vs 264 ± 48 ml/min, p < .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p < .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype. Circulation 75, No. 4, 785-791, 1987. THE ANTIARRHYTHMIC AGENT propafenone is a fast sodium-channel blocker with weak ,3-adrenoceptor-blocking activity and demonstrated efficacy in the treatment of a variety of ventricular and supraventricular cardiac arrhythmias. none is metabolized by an hepatic oxidative pathway that is characterized by the debrisoquine metabolic phenotype. The purposes of this study were to determine in vitro and in vivo the metabolic relationships between debrisoquine and propafenone and to assess the effect of debrisoquine metabolic phenotype, not only on pharmacokinetics, but also on clinical response, concentration-response relationships, and toxicity of propafenone. MethodsPatient selection. Patients were eligible for the study if they were between 21 and 75 years old and had more than 30 ventricular ectopic depolarizations (VEDs) per hour. Antiarrhythmic therapy was indicated for treatment of arrhythmias symptomatic with syncope, near-syncope, dizziness, fatigue, or palpitations. Patients with hemodynamically unstable sustained ventricular tachycardia or a history of sudden cardiac death were excluded, as were patients with second-or third-degree heart block, severe congestive heart failure (functional class IV of the New York Heart Association), hepatic or renal insufficiency, or terminal illness.Determination of debrisoquine phenotype. Debrisoquine phenotype was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine.12' 13 A single 10 mg oral dose of debrisoquine was given 785 Downloaded from http://ahajourn...

The tissue uptake of extensively plasma-bound compounds is reportedly inconsistent with the conventional free-drug hypothesis limiting transport to unbound moiety in rapid intracapillary equilibrium with bound complex. Instead, proteinmediated/cell surface enhancement of dissociation has been postulated to occur in the microvasculature. This possibility was investigated by studying the passive transport of diazepam across the blood-brain barrier. Microdialysis probes placed within the vena cava and brain cortex were used to directly compare steady-state, interstitial unbound diazepam levels in both Wistar and genetically analbuminemic rats. The absence of albumin in the latter increased the unbound fraction of diazepam by almost fivefold; however, in both groups, the ratio of unbound concentrations in brain and blood at equilibrium was equal to unity. If enhanced dissociation occurred in the microvasculature, then the unbound brain level should have been greater than that in the systemic circulation. It is probable that earlier findings suggestive of protein-mediated transport reflect a nonequilibrium phenomenon. Comparison of the extent of diazepam's in vivo binding in blood by microdialysis to that estimated in vitro using conventional equilibrium dialysis with microcells showed good agreement, thus validating a widely accepted assumption of equivalency of these two values.