Elaine Woo
Harvard University
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Clinical Pharmacokinectics | 1980
Hermann R. Ochs; David J. Greenblatt; Elaine Woo
SummaryThe elimination of quinidine in humans is accomplished by a combination of renal excretion of the intact drug (15 to 40% of total clearance) and hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). Many of the metabolites appear to be pharmacologically active. Typical ranges for kinetic properties of quinidine in healthy persons are: apparent volume of distribution 2.0 to 3.5 litres/kg: elimination half-life 5 to 12 hours; clearance, 2.5 to 5.0ml/min/kg. Quinidine clearance is reduced in the elderly, in patients with cirrhosis, and in those with congestive heart failure.Oral quinidine is available either as relatively rapidly absorbed conventional tablets (usually quinidine sulphate) or as a variety of slowly absorbed sustained release preparations. Absolute systemic availability generally is 70% or greater.Quinidine is 70 to 95% bound to plasma protein, primarily to albumin but also to a number of other plasma constituents. Binding is reduced in patients with cirrhosis, partly because of hypoalbuminaemia, but is not influenced by renal insufficiency. Clinical interpretation of total serum or plasma quinidine concentrations must be altered in patients with reduced or increased binding, since it is the unbound fraction which is pharmacologically active.
American Journal of Cardiology | 1978
Hermann R. Ochs; David J. Greenblatt; Elaine Woo; Thomas W. Smith
The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.
American Journal of Cardiology | 1978
Hermann R. Ochs; David J. Greenblatt; Elaine Woo; Kate Franke; Henry J. Pfeifer; Thomas W. Smith
Abstract The pharmacokinetics of oral quinidine sulfate and quinidine gluconate were compared in seven healthy volunteers In a two part pharmacokinetic study. Part I was a single dose crossover trial assessing absorption and elimination of quinidine sulfate (400 mg, equivalent to 331 mg of quinidine base) and quinidine gluconate (495 mg, equivalent to 309 mg of quinidine base). Mean kinetic values for the sulfate and gluconate preparations, respectively, were: peak serum quinidine level 2.07 versus 1.24 μg/ml (P Part II evaluated steady state kinetics of both preparations in a cross-over trial in the same subjects. Maintenance dosing schedules were 200 mg of quinidine sulfate every 6 hours versus 495 mg of quinidine gluconate every 12 hours. Systemic availability of the gluconate at the steady state level was 10 percent less (based upon area under the serum concentration curve) or 7 percent less (based upon urinary excretion of quinidine) than that of the sulfate, but the differences were not significant. Interdose fluctuation in serum quinidine concentrations during the gluconate trial averaged 70 percent, which was not significantly different from the average of 67 percent during the sulfate trial. However, variation within and between subjects in minimal steady state levels with quinidine gluconate (15.6 and 16.0 percent, respectively) was greater than with quinidine sulfate (7.2 and 9.9 percent, respectively). Steady state concentrations during the multiple dose trial were not accurately predicted from single dose pharmacokinetics, either for quinidine sulfate (r = 0.45) or quinidine gluconate (r = −0.12), but deviation of observed from predicted concentrations tended to be greater with quinidine gluconate. The slow absorption of quinidine from the gluconate preparation allows maintenance therapy on a 12 hourly dosage schedule with acceptable interdose fluctuation in serum levels. Variability within and between subjects in absorption kinetics tends to be greater with quinidine gluconate than with the more rapidly absorbed sulfate salt.
Pharmacology | 1978
Hermann R. Ochs; David J. Greenblatt; Elaine Woo; Kate Franke; Thomas W. Smith
5 healthy volunteers received 4–5 mg/kg of quinidine base by 15-min intravenous infusion on two occasions separated by at least 1 week. Multiple venous blood samples and all urine was collected during the 48 h after each dose and were analyzed for concentrations of total and unbound quinidine (following separation by equilibrium dialysis) by a double-extraction spectrophotofluorometric technique. The first quinidine administration was a ‘control’; for the second quinidine administration, propranolol (40 mg orally every 4–6 h) was given, starting 12 h before the quinidine dosage and continuing for the the duration of the trial. A high degree of β-blockade, assessed by intravenous isoproterenol sensitivity, was achieved by propranolol treatment. Mean (± SE) kinetic variables for quinidine during control and propranolol trials, respectively, were: volume of distribution, 3.0 ± 0.5 versus 2.9 ± 0.5 1/kg (NS); elimination half-life, 7.8 ± 1.1 versus 7.6 ± 0.7 h (NS); total clearance, 4.5 ± 0.6 versus 4.3 ± 0.6 ml/min/kg (NS); renal clearance, 1.58 ± 0.2 versus 1.57 ± 0.2 ml/min/kg (NS); percent unbound, 23.0 ± 1.1 versus 23.6 ± 1.3% (NS). Intravenous quinidine produced tachycardia, T-wave flattening, and prolongation of the QT-interval; none of the changes were influenced by propranolol coadministration. Thus propranolol did not significantly alter the pharmacokinetics or acute electrocardiographic effects of intravenous quinidine in healthy volunteers.
American Heart Journal | 1980
Hermann R. Ochs; Eberhard Grube; David J. Greenblatt; Elaine Woo; Gunther Bodem
Ten healthy volunteers received 300 mg. of quinidine base as the gluconate salt by 15-minute intravenous infusion. Physiologic variables monitored before, during, and for 24 hours after the infusion were: electrocardiogram, systolic and diastolic blood pressure, echocardiogram, and carotid pulse tracing. During quinidine infusion, mean ventricular rate increased by 18% (67.1 to 79.5 beats per minute) and corrected QT interval increased by 54% (0.44 to 0.68 sec.). QRS duration did not change significantly, nor did systolic or diastolic blood pressure. Ejection fraction (EF) measured by echocardiography did not decrease during quinidine infusion, but rather increased by 12% (0.58 to 0.65). Mean rate of circumferential fiber shortening (Vcf) likewise increased by 22%, from 1.15 to 1.40 per second. Over the 24-hours post-infusion, all monitored physiologic variables fluctuated considerably; in the case of EF and Vcf, apparently random variations over time were as great as those attributable to quinidine infusion. Mean (and range) kinetic variables for quinidine were: volume of distribution, 2.03 (1.47 to 3.00) liter/Kg.; elimination half-life, 6.3 (4.8 to 7.9) hours; total clearance, 3.8 (2.8 to 5.2) ml./min./Kg. Neither total nor unbound serum quinidine concentrations were significantly correlated with physiologic changes. Thus, intravenous quinidine in the doses studied did not have negative inotropic effects in a series of healthy humans.
American Heart Journal | 1980
Hermann R. Ochs; David J. Greenblatt; Brian L. Lloyd; Elaine Woo; M. Sonntag; Thomas W. Smith
Some of the unwanted effects of quinidine commonly occurring in clinical practice involve the central nervous system. We therefore assessed the rate and extent of quinidine passage into cerebrospinal fluid (CSF) in humans and dogs. In eight human subjects receiving oral quinidine therapy, lumbar CSF quinidine concentrations averaged 16% of unbound serum concentrations (range: 4% to 37%). The findings were confirmed when simultaneous serum (total and unbound) and CSF quinidine concentrations were followed for up to 8 hours after a single intravenous dose of quinidine in anesthetized dogs. Quinidine appeared promptly in CSF of all animals, but CSF concentrations averaged only 37% to 46% of unbound serum levels. The in vitro octanol:water partition coefficient for quinidine at physiologic pH was greater than 100, indicating that unbound quinidine should readily traverse the blood-brain barrier. Thus, passage of quinidine into CSF appears not to be governed by passive diffusion alone. Quinidine may participate in an active transport system such as that which removes certain other basic substances from CSF.
Clinical Pharmacology & Therapeutics | 1980
Elaine Woo; David J. Greenblatt
Eight healthy subjects took single 400‐mg doses of quinidine sulfate in the fasting state, and immediately after a standard breakfast, in a crossover study with at least 1 wk intervening. No other food or liquid was taken for 3 hr after the quinidine. Total and unbound quinidine levels were determined in multiple serum samples and in all urine collected for 48 hr thereafter. Mean systemic availability of quinidine in fasting and postprandial states based on area under the serum concentration curve (19.0/19.1 μg/ml × hr), or on cumulative urinary excretion (85.3/90.8 mg), did not differ. Compared with the fasting state, postprandial doses led to lower peak total serum quinidine levels (1.96/1.73 μg/ml) reached later after the dose (1.47/2.41 hr) and longer absorption half‐life (½) (31.6/37.7 min) but none of these differences was significant. Actual differences were, in fact, considerably greater because of lower protein binding in the fasting (27.5% unbound)/postprandial (23.2%/unbound) state (p < 0.05). Peak unbound quinidine levels averaged 34% lower (0.65/0.43 μg/ml, p < 0.1), and were reached later (1.26/2.75 hr after dose, p < 0.025) in the postprandial trial. Thus, administration of quinidine with a standard breakfast did not influence total systemic availability but slowed the appearance in serum of unbound quinidine, partly due to increased serum protein binding in the postprandial state. This may explain the lower frequency and severity of quinidine‐attributed side effects (nausea, diarrhea, nasal congestion, and palpitations) in the postprandial trial.
Angiology | 1978
Elaine Woo; David J. Greenblatt; Hermann R. Ochs
From the Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts. The antiarrhythmic effect of quinidine has been recognized since 1749. Until recently, however, the choice of a particular quinidine preparation, as well as the appropriate dose and dosage schedule, has been largely empirical, based upon trial-and-error and clinical impression. The development of specific and sensitive assays for quinidine in biological fluids has facilitated pharmacokinetic studies of quinidine, which in turn have allowed a more rational approach to therapy. Effective pharmacotherapy of cardiac arrhythmias generally requires achievement and maintenance of therapeutic blood and tissue levels of an appropriate antiarrhythmic agent. The therapeutic range of quinidine appears
The Journal of Clinical Pharmacology | 1981
David J. Greenblatt; Elaine Woo
Abstract: A series of 26 randomly selected serum samples from patients receiving long‐term antiarrhythmic therapy with oral quinidine preparation were assayed by both a modification of the extraction fluorescence technique and high‐pressure liquid chromatography, with highly comparable results (r = 0.98). A review of the literature on comparing the extraction fluorescence techniques results with other methods indicates a high degree of agreement. However, because variations from study to study exist, investigators using the extraction fluorescence technique should assess the specificity of the method in their own laboratory.
Archive | 1978
Hermann R. Ochs; David J. Greenblatt; Elaine Woo; Kate Franke
Seit kurzem ist bekannt, das Propranolol (P) die Pharmakokinetik anderer Arzneimittel erheblich beeinflussen kann: So verlangert eine P-Therapie beim Menschen die Halbwertzeit von Antipyrin um mehr als 40% und vermindert die Anitipyrin- Clearance um 30%. Am Hund konnten Shand et al. zeigen, das die Lidocain-Clea- rance bei gleichzeitiger P-Gabe um 24% verringert und die HWZ um 48% verlangert wird. Wir haben daher untersucht, ob die Pharmakokinetik von i.v. appliziertem Chinidin sowie die durch Chinidin bedingten EKG-Veranderungen unter einer gleichzeitigen P-Gabe beeinflust werden.