Clinical implications of patient-provider agreements in opioid prescribing.

In June, 2012 the United States Food and Drug Administration (FDA) developed a "blueprint" for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

Improving the effect of FDA-mandated drug safety alerts with Internet-based continuing medical education.

The US Food and Drug Administration (FDA) requires risk communication as an element of Risk Evaluation and Mitigation Strategies (REMS) to alert and educate healthcare providers about severe toxicities associated with approved drugs. The educational effectiveness of this approach has not been evaluated. To support the communication plan element of the ipilimumab REMS, a Medscape Safe Use Alert (SUA) letter was distributed by Medscape via email and mobile device distribution to clinicians specified in the REMS. This alert contained the FDA-approved Dear Healthcare Provider (DHCP) letter mandated for distribution. A continuing medical education (CME) activity describing ipilimumab toxicities and the appropriate management was simultaneously posted on the website and distributed to Medscape members. Data were collected over a 6-month period regarding the handling of the letter and the responses to pre- and post-test questions for those who participated in the CME activity. Analysis of the answers to the pre- and posttest questions showed that participation in the CME activity resulted in an improvement in correct answer responses of 47%. Our experience shows that there are likely distinct information sources that are utilized by different HCP groups. The ready availability of a brief CME activity was utilized by 24,063 individuals, the majority of whom showed enhanced understanding of ipilimumab toxicity by improvement in post-test scores, educational data that are not available via implementation of standard safety alert communications. These results demonstrate that improvement in understanding of specific drug toxicities is enhanced by a CME intervention.

The practicing clinician and regulatory safety concerns.

Pharmaceutical agents are prescribed to produce a therapeutic effect, but safety concerns require constant attention to the benefit:risk relationship inherent in their use and the needs of the individual patient. Such calculations involve assumptions about the likely tolerability of harm, in that greater safety risks may be acceptable for use of a lifesaving drug, compared with those acceptable for an agent providing only improved "quality of life." Making such assumptions is an activity integral to the bedside clinician's role, is done during many (perhaps most) patient encounters, and is often undertaken with inadequate information. The historical mandates for regulatory agencies, such as the Food and Drug Administration (FDA) in the United States, have evolved over the past decades to include an intense focus on drug safety. Communicating information about medicinal risk remains a major responsibility for the FDA and similar bodies, but the initiatives undertaken have had variable, and often limited, effectiveness in penetrating the physician-patient interaction. Barriers to the successful communication of safety-related issues include the myriad of influences on and within the FDA, the time constraints on physicians involved in clinical practice, and the methodologies used to share information about both established and new drugs. Current efforts to assess the effectiveness of regulatory efforts at risk communications should lead to changes in the approaches used and, ultimately, improvement in the safe use of both new and established drugs.

Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2.

This study was designed to determine plasma glucose and insulin levels after administration of three escalating doses of the oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in fasting, insulin-deprived adult patients with type 1 diabetes. The study was also designed to assess the safety of the product. Sixteen patients with daily insulin requirements of 27-60 units and glycosylated hemoglobin levels of 5.8-11.1% completed the study. Patients' regular insulin regimens were discontinued at bedtime, and they fasted overnight. Blood glucose levels were stabilized overnight by intravenous insulin infusion. In the morning, intravenous insulin was discontinued 30 min prior to an oral dose of HIM2 (0.6, 0.8, or 1.0 mg/kg). A second oral dose of HIM2 was administered 120 min later. Plasma glucose and insulin levels were measured during a 240-min evaluation period after the first HIM2 dose. Identical HIM2 dosing and study procedures were repeated 1 week later with the same patients. Stable or declining plasma glucose levels were observed on 31 out of a total of 32 dosing days beginning at 20 min after the initial administration of HIM2. After plasma glucose levels declined or were stable for 30 min to 2 h, increases were observed for some patients. However, for the majority of patients (68.8%), plasma glucose levels were <150% of predose levels throughout the postdose evaluation period. Similar results were observed after repeating the study procedures 1 week later. Also, plasma glucose area under the concentration-time curves (AUCs) were inversely correlated with plasma insulin AUCs. HIM2 appeared to be safe and well-tolerated in this study; no episodes of symptomatic hypoglycemia were observed. Thus, HIM2 prevented the expected rise in plasma glucose concentrations in insulin-deprived adult patients with type 1 diabetes. The lack of hypoglycemic events in this exploratory study is encouraging and suggests that there may be less risk of severe hypoglycemia associated with HIM2 when compared with injectable insulin. The promising data in this study support the hypothesis that oral HIM2 reproduces the physiological pathway of insulin secreted by the pancreas - through the portal vein directly to the liver - suggesting a therapeutic advantage in the management of type 1 diabetes mellitus.

Cardiodepressant actions of combined diltiazem and propranolol in dogs.

The cardiovascular actions of combined intravenous (i.v.) diltiazem and propranolol were studied in barbiturate-anesthetized dogs. When given alone, diltiazem increased cardiac output (CO) and P-R interval duration (P-R) while decreasing mean arterial pressure (MAP), heart rate (HR), and systemic vascular resistance (SVR). Propranolol alone decreased CO and HR while increasing SVR. With the same i.v. doses, combined infusion of diltiazem and propranolol rapidly resulted in depression of CO to levels similar to those achieved with propranolol beta-adrenoceptor blockade alone. The combination decreased MAP to levels achieved with diltiazem-induced calcium channel blockade. P-R increased beyond the durations produced by either drug given alone. Pharmacokinetic interactions were not apparent, although slight increases in propranolol plasma concentrations were observed during combined drug infusions. These studies support clinical observations that the cardiovascular effects resulting from a combination of diltiazem and propranolol may be attributed to the characteristic cardiovascular actions of each individual drug.

A multicenter comparison of isradipine and prazosin for treatment of essential hypertension.

Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

Negative inotropic effect of intravenous nifedipine in coronary artery disease: relation to plasma levels.

The relative extent of the vasodilator versus direct negative inotropic effects of nifedipine was studied in 15 male patients with documented coronary artery disease and normal left ventricular function. At the time of diagnostic cardiac catheterization, three groups of five patients received dose of 1, 2, and 3 mg intravenous nifedipine at a rate of 0.33 mg/min. Hemodynamic measurements and blood collections were made before, during, and every 5 minutes for 30 minutes after infusion of nifedipine. Heart rate increased and mean arterial pressure decreased significantly after the 2 and 3 mg doses of nifedipine. Systemic vascular resistance was significantly decreased and cardiac index increased after all doses of nifedipine. Maximal left ventricular dp/dt (dp/dtmax) was significantly decreased after the 3 mg infusion. The reduction in dp/dtmax was most consistent with a reduction in left ventricular contractility as opposed to changes in loading conditions. Plasma concentrations of nifedipine were significantly correlated with bidirectional changes in dp/dtmax (r = 0.86). Nifedipine concentrations below 28.2 ng/ml were associated with a rise in dp/dtmax, whereas concentrations above that level were associated with a reduction in dp/dtmax. These data indicate that intravenous nifedipine produces dose- and concentration-dependent depression of myocardial contractility in patients with coronary artery disease. Nifedipine concentrations associated with negative inotropic effects are readily achievable with common oral and sublingual doses.

Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations.

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

Hemodynamic and pharmacokinetic aspects of the interactions between verapamil and pindolol.

Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.

Kinetics and dynamics of nifedipine after oral and sublingual doses.

Nifedipine is frequently administered by the sublingual route to provide rapid onset of intense effect, especially in patients in whom urgent reduction of elevated blood pressure is indicated. Previously available data, however, suggest that peak levels of nifedipine are higher and occur earlier when the drug is administered orally. Results of pharmacodynamic studies show that maximal hypotensive effects occur between 30 and 60 minutes after administration by either route, but that such effects are often achieved earlier when the drug is given orally. Recent work implies that the absorption of nifedipine through the buccal mucosa is poor, if it occurs at all, and that the appearance of nifedipine in plasma requires delivery of the drug to the stomach for active absorption. The small time lag in absorption that may be attributed to the dissolution of the nifedipine capsule may be obviated by biting through the capsule and swallowing the contents; this bite-and-swallow approach to dosing provides the most rapid rise in plasma nifedipine concentrations, and produces peak levels well above those achieved with sublingual administration.

Kinetics and dynamics of calcium entry antagonists in systemic hypertension.

The calcium-entry antagonists verapamil, diltiazem and nifedipine (and their analogs) are all eliminated by hepatic metabolism and the rate of disposition is dependent on the rate of liver blood flow. During long-term administration, the profound hemodynamic effects of these agents result in changes in hepatic blood flow in association with decreases in arterial pressure, and either increases or decreases in measured cardiac output. This alters the drug's rate of delivery to the site of elimination, with concomitant changes in systemic clearance and a prolongation in elimination half-life. The pharmacokinetic data determined after initial single doses, therefore, only suggest the kinetic characteristics during long-term administration, because this profile depends on the drugs' sustained effects on liver blood flow. The elimination half-life of all 3 prototypical calcium antagonists is probably significantly prolonged during long-term dosing with clinically effective regimens. Patients with hepatic disorders in which liver blood flow is altered, such as cirrhosis, have profound changes in pharmacokinetics with both short- and long-term administration of verapamil and are likely to have similar changes with other calcium antagonists. During short-term administration, the plasma concentrations of verapamil and other calcium antagonists relate closely to the observed hemodynamic (and electrophysiologic) effects. With long-term administration, however, these correlations are much less impressive. When given in tablet form, nifedipine lowers blood pressure roughly in proportion to plasma levels between 20 and 200 ng/ml; verapamil plasma levels between 80 and 800 ng/ml are associated with antihypertensive efficacy. Plasma level measurements, therefore, are not of clinical importance as guides to antihypertensive therapy, except to identify noncompliance or abnormal patterns of drug handling.

Age-related changes in drug handling in man.

Persons older than 65 years constitute 10% of the U.S. population but require approximately one-third of its health care service. A significant proportion of their disease states is related to adverse reactions to prescribed drugs. The origins of this disturbingly high incidence of untoward consequences from drug therapy are multiple and complex. They include: (1) alterations in expected patterns of drug handling associated with physiologic changes of the aging process itself, (2) alterations in responsiveness to specific types of drugs and (3) frequent occurrence of chronic and acute diseases. The data documenting pharmacokinetic changes in aging subjects are rudimentary, and the physician is commonly aware only of pharmacokinetic profiles derived from studies in healthy, young subjects. Without a firm basis on which to rest pharmacologic therapy, the clinical approach to drug treatment in the elderly patient must be cautious and conservative.

Aspects of the clinical pharmacology of nifedipine, a dihydropyridine calcium-entry antagonist.

Although nifedipine has been characterized in terms of its general vasodilatory effects, this dihydropyridine must still be regarded as investigational with regard to available pharmacokinetic and pharmacodynamic data. Although limited studies are available, it is clear that the pharmacokinetic and pharmacodynamic data reported are quite variable among subjects. Further, it appears that single dose elimination kinetics may be of little predictive value with regard to the kinetic characteristics present during chronic drug administration. It is also possible that the plasma level-effect correlations for the drug may differ with single and sustained dosing regimens. At the present time the lack of definitive data to define the relationships between plasma levels of nifedipine and associated drug effects suggests that measurement of drug levels in plasma serves primarily as a research tool and to identify patient noncompliance or abnormal absorption of the drug. Finally, since the prototype of this class, nifedipine, has been shown to have the potential for non-linear kinetics during chronic dosing, dihydropyridine analogs should be subject to extensive pharmacokinetic and pharmacologic evaluation during both single and chronic dosing studies, prior to widespread clinical use.

Verapamil-induced changes in central conduction in patients with multiple sclerosis.

The electrophysiological characteristics of demyelinated axons are sensitive to changes in plasma calcium concentration. This study investigated the effect of verapamil, a calcium antagonist drug, on brainstem auditory, visual, and somatosensory evoked potentials in multiple sclerosis patients. Eight clinically stable patients with abnormal visual and/or brainstem auditory evoked potentials and four normal volunteers were studied. During intravenous infusions of verapamil (mean plasma concentration = 130.0 +/- 56.4 ng/ml), the latencies of peaks III and V were shortened (p less than 0.05) in multiple sclerosis patients with abnormally prolonged BAEPs. The I-III (delta = 0.08 ms), III-V (delta = 0.46 ms), and I-V (delta = 0.53 ms) interpeak intervals, and the P100 latency (delta = 10.15 ms) of the visual evoked potential were similarly affected in these patients. In contrast, normal evoked potentials of both multiple sclerosis patients and control subjects were not altered compared to baseline recordings obtained 24 hours earlier. Intravenous verapamil, therefore, alters the BAEPs and VEPs of some multiple sclerosis patients with demyelinated auditory and visual pathways by shortening pathologically prolonged latencies toward normal. The present study suggests pharmacological manipulation of calcium-dependent processes, possibly at the level of the demyelinated axon, can acutely facilitate central conduction of electrical impulses in some patients with clinically stable multiple sclerosis.

Effect of nifedipine on gastric emptying in normal subjects.

We studied the effects of the calcium-channel blocker, nifedipine, on solid and liquid phases of gastric emptying in 10 healthy male volunteers. Each subject underwent a dual-isotope radionuclide gastric emptying determination with and without the preadministration of nifedipine, 30 mg orally, given 20 min prior to ingestion of the test meal over 10 min, following which the subject lay supine under the gamma-counter for 2 hr. Blood samples for measurement of plasma nifedipine concentration were obtained at the time of drug administration and every 30 min throughout the gastric emptying determination. There was a threefold variation in the areas under the plasma nifedipine concentration vs time curve (AUC) obtained in these 10 subjects. Percent gastric retention of either the liquid (water) or the solid (chicken liver) marker was not significantly different after 30 mg oral nifedipine, as compared to the nontreatment day. We concluded that plasma nifedipine concentrations previously reported to be associated with significant esophageal motility effects in humans were not associated with effects on gastric emptying of either liquids or solids.

Efficacy of verapamil in exercise-induced ventricular tachycardia.

The antiarrhythmic efficacy of verapamil was determined by serial treadmill testing in 16 patients with reproducible exercise-induced ventricular tachycardia (VT). Twelve of the 16 patients responded to verapamil, 0.2 mg/kg intravenously; in 8 of these 12 responders, an oral verapamil regimen of 160 to 320 mg given every 8 hours also prevented exercise-induced VT. Plasma verapamil concentration was significantly higher in the responders than in the nonresponders to intravenous verapamil, but levels were similar in responders and nonresponders to oral therapy. The 8 responders to the oral drug were followed up while receiving verapamil therapy for 6 to 22 months (mean 15), and exercise-induced VT did not recur in any patient. Five of the 8 responders also had concomitant spontaneous VT unrelated to exercise which verapamil suppressed initially as well: 4 remained free of spontaneous VT, while 1 patient had recurrence of spontaneous VT. Thus, in patients with exercise-induced VT, verapamil is a promising alternative therapy to beta-adrenergic blocking agents. The effectiveness of verapamil is consistent with a mechanism of arrhythmogenesis involving calcium channels.

Cardiovascular and pharmacokinetic consequences of combined administration of verapamil and propranolol in dogs.

Verapamil and propranolol, alone and in combination, were given intravenously to anesthetized dogs to analyze the interaction between drug-induced cardiovascular effects and the resulting changes in pharmacokinetics. Dosing regimens were used that produced steady state plasma levels of both drugs, and the observed effects were clearly related to the plasma concentrations of the agents. When given alone, at stable "therapeutic" levels in plasma, verapamil or propranolol decreased spontaneous heart rate, increased atrioventricular conduction time, and had opposite effects on cardiac output. At the same doses, the combined infusion of the 2 drugs rapidly resulted in profound depression in cardiac function; in addition, plasma concentrations of both agents increased into ranges associated with cardiovascular toxicity. When verapamil doses were reduced, combined infusion with propranolol decreased atrioventricular conduction and cardiac output, but drug plasma concentrations (and associated effects) remained stable. When reduced doses of propranolol were added to infusion of verapamil, similar effects on cardiovascular function occurred, but plasma drug levels increased progressively throughout the remainder of the study period. In all combinations studied, beta blockade with propranolol decreased liver plasma flow and, therefore, the systemic clearance of verapamil. The in vitro effects of propranolol on verapamil metabolism were small, although significant, and not clinically relevant. These acute studies suggest that the hemodynamic effects resulting from verapamil and propranolol in combination may significantly diminish clearance of 1 or both drugs, thereby resulting in accumulation during continued administration, increased drug effects with increasing plasma concentrations, and potentially lethal drug toxicity.

Pharmacodynamic comparison of verapamil and nifedipine in anesthetized dogs.

The relationships between steady-state plasma concentrations of verapamil or nifedipine and the resultant hemodynamic and electrophysiologic effects were evaluated in anesthetized, instrumented dogs. In different groups of animals, the drugs were given intravenously by loading-maintenance infusions designed to rapidly achieve and sustain stable plasma drug concentrations, over four different target ranges which span those found in clinical use of these agents. Plasma levels of nifedipine varied from 5 to 125 ng/ml, and those of verapamil, from 40 to 500 ng/ml. Nifedipine produced no apparent effects on the surface electrocardiogram. Verapamil dosing resulted in progressive prolongation of the PR interval as plasma drug levels increased from 40 to 250 ng/ml; at higher drug levels, complete atrioventricular block occurred. At the highest plasma concentrations used, the maximal vasodilation produced by both drugs was approximately equal, with mean aortic pressure levels falling to 50-60% of control values. The effects of the two agents on cardiac pump performance, however, differed: nifedipine administration produced dose-related increases in cardiac output at all plasma drug concentrations studied; the effects of verapamil were critically dependent upon drug levels in plasma, with cardiac output increased above control values at drug concentrations between 40 and 250 ng/ml, and progressively depressed at higher plasma levels of the drug. As a result, the calculated systemic vascular resistance declined progressively during nifedipine administration, while after verapamil doses, this parameter varied inversely with observed effects on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of plasma levels of nifedipine and cardiovascular effects after sublingual dosing in normal subjects.

Only limited work has been reported about the relationships of cardiovascular effects and plasma concentrations of the calcium-channel blocker nifedipine. In this study, placebo and nifedipine in 10-, 20-, 30-, and 40-mg doses were administered sublingually to ten normal subjects with at least three days between dosing periods. Blood pressure and heart rate were monitored every 30 minutes for two hours, and blood samples were taken after each measurement for determination of plasma nifedipine concentration by a sensitive and specific gas chromatographic method. Systolic blood pressure fell significantly (P less than 0.05) although briefly after 10 mg, but the effect persisted with larger doses. Diastolic blood pressure fell significantly only after 30- or 40-mg dosing. Heart rate increased significantly after all doses of nifedipine with the effect lasting longer with higher doses. Systolic blood pressure measurements were significantly related to the log of the concurrently measured plasma nifedipine concentrations (r = -.82, P less than 0.001). Diastolic blood pressure was also related to log nifedipine concentration (r = -.69, P less than 0.01). Heart rate, too, was linearly related to the log of nifedipine plasma levels (r = .75, P less than 0.001). These data indicate that the hemodynamic effects observed after acute nifedipine administration may be used to estimate whether or not significant quantities of the drug are being absorbed and that the intensity of the hemodynamic effects may, therefore, serve as a bioassay to evaluate the appearance of drug in plasma in therapeutic quantities.

Effects of phenobarbital and SKF-525A on in vitro hepatic metabolism of verapamil and nifedipine.

Both verapamil and nifedipine are first-generation calcium-entry antagonist drugs which are eliminated by hepatic metabolism. To evaluate the effects of enzyme induction and suppression on the biotransformation of these compounds, liver homogenate fractions were prepared from male Fisher (F344) rats, which were either untreated, or injected intraperitoneally with phenobarbital or with SKF-525A prior to sacrifice. Known concentrations of verapamil or nifedipine were incubated with the 9,000 g supernatant, and the quantity of unchanged drug remaining after 10 min was measured. SKF-525A pretreatment significantly decreased the elimination (disappearance) rate of both calcium-entry antagonist compounds. Phenobarbital increased the rate of disappearance of verapamil, but had no effect on that of nifedipine. Difference spectra of hepatic microsomes to which verapamil had been added revealed a concentration-dependent, saturable interaction between drug and enzymes with spectral changes characteristic of "type I' substrates for cytochrome P-450 monooxygenase(s). The spectral characteristic of microsomes to which nifedipine was added could not be determined because of drug absorption at 350-500 nm. These data imply that verapamil metabolism is mediated by the cytochrome P-450 monooxygenase(s), and that nifedipine metabolism likely involves hepatic enzyme systems other than those known to be induced by phenobarbital.