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A J Atkinson

Publications and source records attributed to A J Atkinson.

At least 19 recordsLinked to original sources
PubMed1992

Kinetic analysis of P-glycoprotein-mediated doxorubicin efflux.

P-glycoprotein lowers the intracellular concentration of a variety of unrelated compounds including doxorubicin by actively removing them from the cell. Mathematical modeling techniques have been applied to the transmembrane transport of doxorubicin in a nonresistant HL-60 cell line and in a P-glycoprotein-containing resistant subclone, HL-60R, to obtain clearances for inward and outward transport. Distribution of [14C]doxorubicin from extracellular fluid into the cell pellet was analyzed with a closed two-compartment system that fitted experimental measurements of drug concentrations in the extracellular fluid and in the cell pellet, represented by a third compartment that includes trapped extracellular doxorubicin along with the intact cells. Transmembrane diffusion clearance was similar for the two cell lines (1.00 vs. 1.06 microliters sec-1), yielding an apparent doxorubicin permeability coefficient of 7.4 x 10(-5) cm sec-1. However, the total efflux clearance averaged 0.99 +/- 0.05 microliters sec-1 in HL-60 and 2.29 +/- 0.62 microliters sec-1 in HL-60R. The estimated P-glycoprotein-mediated efflux clearance in HL-60R averaged 1.23 +/- 0.51 microliters sec-1. This experimental approach provides direct estimates of transport parameters in intact cells and should be useful in studying the mechanism of action and interactions of inhibitors of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Response to head-up tilt in cramping and noncramping hemodialysis patients.

Hemodialysis-associated skeletal muscle cramps are generally ascribed to a reduction in plasma volume, but during this procedure, it is not known how volume contraction results in cramps. To elucidate this mechanism, we compared responses to one hour of 60 degrees head-up tilt in 8 patients who cramped during no more than one-sixth of their dialyses and in 8 patients who cramped at least half the time. Age and recumbent blood pressure were similar in each group, but more patients with frequent cramps had diabetes underlying their renal failure (p = 0.013) and had been dialyzed for less than 3 years (p = 0.020). Baseline plasma renin activity and plasma norepinephrine and arginine vasopressin concentrations were similar in both groups, except plasma renin activity in one patient with frequent cramps, which was 15 times higher than in the other patients. After tilting, systolic blood pressure fell an average of 17% in patients who cramped infrequently (p = 0.0031) but only 10% in frequently cramping patients. The ratio of tilt/recumbent norepinephrine levels exceeded 1.5 in 7 patients with frequent cramps but was less than this in 6 patients who cramped infrequently (p = 0.020). One of the 2 infrequently cramping patients with a ratio above 1.5 was the only individual to have a normal renin response to tilt. We propose that cramps are prone to occur during hemodialysis in patients whose sympathetic nervous system response to volume stress is partially intact but is not modulated by concurrent activation of the renin-angiotensin system.

Adult↗
PubMed1991

Physiological basis of multicompartmental models of drug distribution.

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Animals↗
PubMed1991

Kinetics of D-xylose absorption in patients with human immunodeficiency virus enteropathy.

D-Xylose absorption was studied in 12 patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had had diarrhea for more than 8 weeks, averaged an 11% (range, 3% to 21%) body weight loss during the previous 6 months, and had had negative stool examinations for enteric pathogens. Patients were evaluated by duodenal aspiration and biopsy and received both 25 gm oral and 10 gm intravenous doses of D-xylose. Kinetic analysis of D-xylose absorption was characterized by an absorption rate constant (ka) and a rate constant (ko) reflecting nonabsorptive loss. Extent of D-xylose absorption averaged 18.4% +/- 9.3% (+/- SD) in the 12 patients (normal greater than 60%). Percentage of weight loss during the previous 6 months was negatively correlated with ka (r = -0.69; p = 0.018) in the 11 patients in whom this parameter was reduced but was not correlated with either ko or extent of D-xylose absorption. In these patients with human immunodeficiency virus enteropathy, ka was reduced out of proportion to the minor histologic changes present in the duodenal biopsy specimens.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women.

Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 +/- 0.3 gm/dl (+/- SD) in pregnant subjects, compared with 4.4 +/- 0.3 gm/dl in control subjects (p less than 1 x 10(-6], and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 +/- 1.0) than in nonpregnant (N = 3.3 +/- 0.4) subjects, but binding affinity (ka) averaged only 227 +/- 69 (mol/L)-1 in pregnant subjects, compared with 303 +/- 44 (mol/L)-1 in control subjects (F2,17 = 4.26; p = 0.032). At a theophylline plasma concentration of 10 micrograms/ml, the combined effects of hypoalbuminemia and lowered ka would reduce theophylline binding to 31% +/- 3% in pregnant women, compared to 39% +/- 3% in nonpregnant control subjects (p less than 1 x 10(-5]. Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy-associated decrease in theophylline binding.

Adult↗
PubMed1990

Activation of renin-angiotensin system does not cause skeletal muscle cramps during hemodialysis.

Activation of the renin-angiotensin system usually occurs during hemodialysis and in hemodialyzed normal dogs parallels reductions in blood flow to a tissue group that is largely composed of skeletal muscle. To determine if excessive activation of this system might cause dialysis-associated skeletal muscle cramps in some patients, we conducted a double-blind, randomized and balanced trial in which 5 patients with frequent dialysis-associated cramps were each given either a 25 mg oral dose of captopril or placebo 1 h before 8 consecutive dialyses. Captopril increased the frequency of dialyses complicated by skeletal muscle cramps in 1 patient and did not affect cramp frequency in the other 4 patients. Predialysis plasma renin activity (PRA) averaged 3.9 ng/ml/h (+/- SD) and was the same as in unselected hemodialysis patients. Following captopril, PRA increased by an average of 2.2 +/- 0.7 times, similar to the 2.6-fold increase that was reported when this drug was used to prevent dialysis-associated hypertensive crises. However, hemodialysis by itself did not activate the renin-angiotensin system as consistently in patients with frequent dialysis-associated skeletal muscle cramps as in unselected hemodialysis patients and the ratio of post- to predialysis PRA averaged 1.0 +/- 0.6. We conclude that the renin-angiotensin system does not mediate, and that its activation during hemodialysis may actually help prevent, dialysis-associated skeletal muscle cramps.

Aged↗
PubMed1989

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

Absorption↗
PubMed1989

Splanchnic tissues are a major part of the rapid distribution spaces of inulin, urea and theophylline.

Distribution of kinetics of inulin, [14C]urea and theophylline were studied in five anesthetized dogs after splenectomy and gastrointestinal resection. Distribution was modeled with three-compartment mammillary systems in which the central compartment corresponds to intravascular space and the two peripheral compartments have different rates of transcapillary exchange. Compared with results in intact dogs, the surgical procedure removed between 41 and 55% of the rapidly equilibrating tissues and reduced the permeability coefficient-surface area products for the rapidly equilibrating inulin and urea compartments proportionately. This is consistent with the concept that splanchnic organs equilibrate rapidly with inulin and urea because they are supplied by fenestrated and discontinuous capillaries that are prominent in the splanchnic vascular bed. However, splanchnic organs probably do not contain all rapidly equilibrating tissues, and somatic tissues may contribute as much as 36 and 22%, respectively, of the rapidly equilibrating inulin and urea compartments. Cardiac output averaged 2.87 +/- 0.86 liters/min and was similar to the sum of compartmental blood flows estimated from the intercompartmental clearances of urea and inulin (2.74 +/- 0.96 liters/min) and to the sum of theophylline intercompartmental clearances (2.62 +/- 0.74 liters/min). Theophylline intercompartmental clearance to each peripheral compartment was similar to estimated compartmental blood flow.

Animals↗
PubMed1988

Comparison of the pharmacokinetic and pharmacodynamic properties of procainamide and N-acetylprocainamide.

Although procainamide (PA) has been widely used to treat patients with both ventricular and supraventricular arrhythmias since 1951, more than twenty years elapsed before N-acetylprocainamide (NAPA) was identified as a major PA metabolite and shown in PA-treated patients to have plasma concentrations generally equaling or being 2 to 3 times greater than those of the parent drug. Numerous investigations have been conducted since then to characterize the pharmacokinetics and pharmacodynamics of NAPA and to compare these properties with those of PA. Salient differences have been that the elimination half-life of NAPA is 2.5 times that of PA, even when renal function is normal; that NAPA has a spectrum of electrophysiologic action that differs from PA in that NAPA only prolongs action potential duration; and that NAPA is less likely than PA to cause a syndrome resembling systemic lupus erythematosus. Although these properties have provided an impetus for the development of NAPA as an antiarrhythmic drug in its own right, emphasis is placed in this review on the implications of these findings for individualizing PA therapy.

Acecainide↗
PubMed1987

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation.

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.

Acecainide↗
PubMed1986

Pharmacokinetics of N-acetylprocainamide.

Shortly after Dreyfus and his colleagues demonstrated that procainamide was metabolized by acetylation to N-acetylprocainamide (NAPA), Drayer, Reidenberg and Sevy reported that NAPA had antiarrhythmic activity in an animal model. We confirmed these findings and found that plasma levels of NAPA were high enough to warrant consideration in managing patients requiring procainamide therapy. However, the actual impetus for developing NAPA as an antiarrhythmic drug in its own right was provided by the initial studies of NAPA pharmacokinetics in normal subjects. In these studies, we showed that NAPA has an elimination-phase half-life that is more than twice as long as procainamide and suggested that patient compliance and arrhythmia suppression might be improved if NAPA were used to circumvent the inconvenience of the frequent dosing schedule that has been recommended for procainamide. From the standpoint of managing individual patients with NAPA, the pharmacokinetics of this drug continue to provide the scientific basis for designing dose regimens that will have maximal antiarrhythmic efficacy and minimal toxicity. This review summarizes the salient features of NAPA pharmacokinetics and outlines an approach for individualizing therapy with this drug.

Acecainide↗
PubMed1979

Long-term antiarrhythmic therapy with N-acetylprocainamide.

The effects of long-term NAPA therapy were evaluated in 6 patients with chronic PVCs known to respond to this drug during a previous placebo-controlled, dose-ranging trial. Underlying cardiac status was evaluated every six months by switching each patient from NAPA to placebo. Placebo period PVC frequency after one year of NAPA therapy was reduced, compared to baseline placebo values. Mean PEP/LVET, measured while the patients received placebo, was elevated at the beginning of the study but was normal after one year of NAPA therapy. Comparison of NAPA and placebo period observations indicated a reduction in PEP/LVET when NAPA therapy was begun. This effect, however, could not be demonstrated one year later when mean placebo period PEP/LVET was normal. The apparent dependence of this effect on underlying status of left ventricular function suggests that the initial reduction in PEP/LVET represents an an indirect effect of NAPA rather than a direct inotropic action. NAPA therapy was well tolerated by the 6 patients and ANA titers became abnormal in only one, in marked contrast to reported experience with procainamide.

Aged↗
PubMed1979

N-Acetylprocainamide pharmacokinetics in functionally anephric patients before and after perturbation by hemodialysis.

NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t 1/2 of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClT approximately fourfold. Dialysis itself resulted in a 77% reduction in ClS that limited the total amount of NAPA removed by this procedure. This reduction in ClS was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.

Acecainide↗