Studies were performed in 13 healthy subjects to determine whether treatment with rifampicin results in induction of the metabolism of mephenytoin. Daily dosing with 600 mg rifampicin for 22 days caused a three to eightfold increase in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug to extensive metabolizers of the anticonvulsant. This was accompanied by a 40 to 180% increase in the 0-8 h urinary excretion of the 4'-hydroxy metabolite. Four weeks after discontinuing rifampicin, both metabolic indices had returned to their baseline values. By contrast, rifampicin had no effect on either measures of metabolism in subjects of the poor metabolizer phenotype. Thus, it appears that the activity of the enzyme (P-45OMp) mediating the genetically determined 4'-hydroxylation of S-mephenytoin can be significantly modulated by enzyme inducing agents such as rifampicin and possibly environmental agents with a similar ability.Keywords mephenytoin genetic polymorphism induction of metabolism rifampicin interaction

No abstract

Propafenone is an antiarrhythmic drug that produces a variable degree of P3-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and p3-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73+±0.15 (mean+SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the SIR ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte 1-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (K, 7.2±2.9 nM) than for the (-)-R-enantiomer (K;, 571±141 nM). We conclude that during relation has been reported. One explanation for this variability is the genetically determined impairment in approximately 7% of the Caucasian population to metabolize propafenone.1 This polymorphism cosegregates with the ability to 4-hydroxylate the antihypertensive debrisoquine and correlates with the functional presence or absence of the hepatic cytochrome P-450db1.6 Patients with the extensive metabolizer phenotype (EM) or the poor metabolizer phenotype (PM) can be distinguished,' and the metabolic pathway affected by polymorphic oxidation is the formation of the active metabolite 5-hydroxy propafenone.7,8 Propafenone is administered as a racemic mixture of (+)-S-and (-)-R-enantiomers. Pharmacokinetic differences between the enantiomers of other racemic drugs, such as metoprolol and N-propylajmaline, which are substrates for P-450db1, have been found in EM but not in PM subjects, indicating the potential for stereoselective metabolism of substrates for this cytochrome P 450.9, 1 The in vitro electrophys-

1A hospital-based drug information system has been used to assess the time for which patients treated with warfarin were outside the range of Thrombotest values 5-10% and 5-15% and to examine possible contributory factors in situations where anticoagulation fell outside these ranges. 2 Anticoagulant control varied with the age of the patient and with concomitant drug therapy but not with patient sex or indication for anticoagulation. 3 Most patients were 'under-anticoagulated' at some stage but patients over 70 years spent significantly longer in the 5-10% range than those in the age range 30-59 years and Thrombotest values of less than 5% were found predominantly in the older group. 4 Patients given drugs known to interact with warfarin spent least time in the defined Thrombotest ranges. Those on drugs known to potentiate warfarin effect had significantly lower Thrombotest values than the other patients studied.

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.