J. L. McNay

Individualization of phenytoin dosage regimens

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis‐Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady‐state phenytoin serum concentrations resulting from different daily doses: The observed steady‐state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p < 0.02). The average deviation between observed and predicted levels was 0.04 µg/ml (range, ±3.2 µg/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r = 0.360, p < 0.05). The average deviation was −3 µg/ml (range, 3.9 to −11.3 µg/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

Hydralazine kinetics after single and repeated oral doses

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid‐labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 μM for the single dose and 0.14 μM for repeated doses in the fast acetylator group and 1.03 μM for the single dose and 0.96 μM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half‐lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.

Plasma concentration and acetylator phenotype determine response to oral hydralazine.

SUMMARY The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of bydralazbe in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator pbenotyping for individualization of hydralazine dosage regimens merits further evaluation.

Thin-layer chromatographic analysis of cocaine and benzoylecgonine in urine

The sensitivity achieved by the described thin-layer chromatographic (TLC) method greatly exceeds that of previously published TLC methods for the determination of cocaine and its principal metabolite, benzoylecgonine, in urine. Sensitivity for cocaine and benzoylecgonine approaches 0.1 and 0.25 mug/ml, respectively, for a 5.0-ml specimen. A simple extraction with a mixed organic solvent provides the basic mechanism for isolating the drugs from biologic specimens. Cocaine and its metabolites are stable in sulfuric acid solutions but labile in aqueous media containing certain other inorganic and organic acids; therefore, an emphasis on the utilization of sulfuric acid solutions is employed throughout the procedure. An evaluation of sensitivities achieved for cocaine and benzoylecgonine by various detection reagents is presented. The technique is applicable to drug screening programs.

Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.

To determine the role of the peripheral sympathetic nervous system in the persistent tachycardia caused by the antihypertensive drug hydralazine, we examined the temporal relationships between the changes in heart rate and plasma norepinephrine concentration and the reduction in blood pressure produced by a range of doses of hydralazine administered intravenously to five hypertensive patients. Significant linear correlations were found between the increases in heart rate and plasma norepinephrine concentration and the reduction in blood pressure at 15 and 30 minutes after injection. However, at 240 minutes after injection, changes in heart rate and plasma norepinephrine were not correlated with changes in blood pressure and were disproportionately elevated relative to the reduction in blood pressure. A significant linear correlation between changes in heart rate and plasma norepinephrine concentration was noted at 15, 30, and 240 minutes after injection. The temporal discordance of the changes of both heart rate and plasma norepinephrine relative to the reduction in blood pressure and the significant linear correlation between the increases in heart rate and plasma norepinephrine concentration suggest that continued activation of the peripheral sympathetic nervous system contributes to the persistent tachycardia seen after the administration of hydralazine.

Quantitative analysis of hydralazine pyruvic acid hydrazone, the major plasma metabolite of hydralazine

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Initial Experience of Clinical Pharmacology and Clinical Pharmacy Interactions in a Clinical Pharmacokinetics Consultation Service

R ECOGNITION of the need for improvement of drug-related health care prompted the conscious promotion of the discipline of clinical pharmacology in many countries in Europe and North America. The direct impact of this discipline on health care delivery (as opposed to research and education) has been limited by the scarcity of medically trained clinical pharmacologists. Delays in the funding of new clinical pharmacology units and inadequate funding of existing units guarantees that these man power problems will persist worldwide for several decades. As a consequence, it is apparent that the necessary delivery of comprehensive drug-related health care cannot be carried out by medically qualified clinical pharmacologists, even if this were judged desirable.’ In the United States, at the urging of senior medical educators2’3 and concerned

Captopril modifies the hemodynamic and neuroendocrine responses to sodium nitroprusside in hypertensive patients.

To determine if clinically effective doses of the antihypertensive agent captopril affected the neuronal release of norepinephrine or baroreflex sensitivity, changes in plasma norepinephrine concentration and heart rate were related to the changes in mean arterial pressure seen during the intravenous infusion of stepwise incremental doses of sodium nitroprusside before and during captopril treatment in eight hypertensive men with normal or low plasma renin activity. At all times, significant linear correlations were found between the decrease in mean arterial pressure and the dose of sodium nitroprusside, the increase in heart rate and the decrease in mean arterial pressure, and the increase in plasma norepinephrine concentration and the decrease in mean arterial pressure. When the subjects were treated with captopril (25 mg t.i.d.) for 2 to 4 weeks, supine mean arterial pressure decreased from 130 to 114 mm Hg (-12%; p less than 0.05), heart rate did not change, supine and upright plasma renin activity increased, while supine plasma norepinephrine and epinephrine concentration decreased slightly. Therapy with captopril (25 mg t.i.d.) increased baroreflex sensitivity, as assessed by the slope of the regression line relating the increase in heart rate to the decrease in mean arterial pressure, and increased the responsiveness of the sympathetic nervous system, as assessed by the slope of the regression line relating the increase in plasma norepinephrine concentration to the decrease in mean arterial pressure. These increases were accompanied by a decrease in the slope of the regression line relating the decrease in mean arterial pressure to the dose of sodium nitroprusside and thus were associated with a decreased sensitivity to the vasodepressor effects of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved assays for hydralazine and hydralazine pyruvic acid hydrazone in human plasma

Abstract Previous determinations of hydralazine and hydralazine pyruvic acid hydrazone based on derivatization and high-performance liquid chromatography have been modified to improve the detection limits of the hydralazine assay and the selectivity of the hydralazine pyruvic acid hydrazone technique. The lower limits of determinations of hydralazine and hydralazine pyruvic acid hydrazone are 2 and 25 ng ml -1 , respectively. The application of this technique to the determination of these substances in human plasma is demonstrated.

Hypotensive effect of the hydralazine--acetone hydrazone in conscious rabbits: evidence for its back-conversion to hydralazine in vivo.

The hydralazine—acetone hydrazone (HAH) has previously been identified as a metabolite of hydralazine (H) in humans. We compared the hypotensive effects of HAH and H in groups of hypertensive rabbits. Both compounds caused a dose-dependent depressor response, with a potency ratio of HAH to H of approximately 0.2. Upon their intravenous administration to anephric rabbits, both H and HAH produced sustained concentrations in plasma of the H-pyruvic acid hydrazone, demonstrating that back-conversion of HAH to H occurred in vivo. We conclude that HAH is hydrolyzed in vivo to yield parent H. The levels of the H-metabolite, the pyruvic acid hydrazone, suggest that the hypotensive effect of HAH could be explained entirely by generation of H in vivo. This combined pharmacokinetic and pharmacodynamic approach can be applied to other H-hydrazones to evaluate their back-conversion to H in vivo.