E. J. Pantuck

Intraindividual variation in drug disposition

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half‐lifes and areas under the plasma concentration‐time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.

Cigarette smoking and chlorpromazine disposition and actions.

Chlorpromazine, 75 mg, was taken by eight cigarette smokers and nine nonsmokers. Mean maximum percent decrease in mean blood pressure with change in position from lying to standing during the first 10 hr after chlorpromazine was 46% greater in nonsmokers than in smokers. Of the eight smokers, six did not become sleepy after chlorpromazine, one became slightly sleepy, and one fell asleep. Of the nine nonsmokers, three became slightly sleepy, one moderately sleepy, and five fell asleep. Mean peak plasma concentration of chlorpromazine was 24% lower and mean area under the plasma concentration‐time curve (AUC) was 36% lower in smokers than in nonsmokers. There was no correlation between these plasma level parameters and either the degree of sleepiness or the degree of orthostatic hypotension in the subjects. The relatively small differences between cigarette smokers and nonsmokers in AUCs and peak plasma levels for chlorpromazine, combined with the lack of relationship between these plasma level parameters, the occurrence of drowsiness, and the magnitude of orthostatic hypotension in our subjects make it unlikely that cigarette smoking influenced these effects of chlorpromazine by enhancing its overall metabolism.

Epidural Analgesia for Labour and Delivery: Fentanyl or Sufentanil

PurposeThe highly lipid soluble opioids, fentanyl and sufentanil, are used in combination with local anaesthetics with/ without epinephrine to provide epidural analgesia during labour and delivery. Our aim was to determine whether either opioid was superior when used with low dose local anaesthetic.MethodsIn a double-blind study patients were randomized to two epidural infusion groups: Group I (n = 50) fentanyl 2 μg · ml−1 with bupivacaine 0.015% and epinephrine 2 μg · ml−1, Group II (n = 50) sufentanil 1 μg · ml−1 with bupivacaine 0.015% and epinephrine 2 μg · ml−1. Following a 20 ml bolus of the study solution an infusion was started at 10 ml · h−1. To achieve analgesia patients could receive two boluses of 5 ml of the study solution and if analgesia was still inadequate, a further 5 ml bupivacaine 0.25% was used. Pain and overall satisfaction were assessed with a 10-point visual scale. Plasma samples obtained from the mother at the time the infusion was discontinued and from the umbilical cord vein at delivery were assayed to determine opioid concentration.ResultsPain scores were greater for Group I than for Group II patients throughout the first and second stages of labour (P = 0.002). More patients in Group I (42%) requested a dose of bupivacaine 0.25% than in Group II (6%) (P < 0.0001) and the total dose of bupivacaine given to Group I patients was greater than that of Group II, 26.0 ± 22.0 mg vs. 13.4 ± 12.6 mg, P = 0.005. There were no differences with respect to first or second stage duration, incidence of side effects, infusion duration, outcome of labour or neonatal Apgar scores. There was no opioid accumulation in either maternal or foetal blood.ConclusionEpidural opioid infusion with very low dose bupivacaine (0.015%) achieved an overall high level of patient satisfaction in both groups without serious maternal or neonatal side effects. At the fentanyl-to-sufentanil ratio used here patients receiving sufentanil had lower pain scores and substantially fewer patients required bupivacaine rescue.RésuméObjectifLes morphiniques hautement liposolubles comme le fentanyl et le sufentanil sont utilisés avec les anesthésiques locaux pour procurer l’analgésie épidurale pendant le travail et l’accouchement avec ou sans épinéphrine. Cette étude visait à déterminer lequel des deux morphiniques était supérieur lorsqu’on l’associait à un anesthésiques local à faible dose.MéthodesL’étude randomisée et en double aveugle incluait deux groupes: le groupe I (n = 50) avait reçu du fentanyl 2 μg · ml−1 et de la bupivacaïne 0,015% avec épinéphrine 2 μg · ml−1 alors que le groupe II (n = 50) avait reçu sufentanil 1 μg · ml−1 et bupivacaïne 0,015 avec épinéphrine 2 μg · ml−1. Après un bolus de 20 ml de la solution à l’étude, une perfusion était débutée au rythme de 10 ml · h−1. Pour compléter l’analgésie, les patientes pouvaient recevoir deux bolus de 5 ml de la solution à l’étude. Si l’analgésie était toujours insuffisante, une dose additionnelle de 5 ml de bupivacaïne 0,25% était administrée. La douleur et le degré de satisfaction étaient évalués sur une échelle visuelle de dix points. Des échantillons de plasma maternal à l’arrêt de la perfusion et du cordon ombilical à l’accouchement ont été analysés pour déterminer la concentration du morphinique.RésultatsQuant à la douleur, les scores ont été plus élevés dans le groupe I que dans le groupe II pendant le premier et le deuxième stage du travail (P = 0,002). Plus de patients du groupe I (42%) ont eu besoin de bupivacaïne 0,25% que dans le groupe II (6%) (P < 0,001) et la dose totale de bupivacaïne administrée aux patientes du groupe I a été plus élevée que dans le groupe II, 26,0 ± 22,0 mg vs 13,3 ± 12,6 mg, P = 0,005. En ce qui concerne la durée du premier et du deuxième stage du travail, la différence était nulle, ainsi que l’incidence des effets secondaires, la durée de la perfusion, l’évolution du travail ou les scores sur l’échelle d’Apgar. On n’a pas noté d’accumulation de morphinique dans le sang maternel ni dans le sang foetal.ConclusionAvec une perfusion de morphinique associée à de très faibles doses de bupivacaïne (0,015%), en général, le degré élevé de satisfaction a été élevé dans les deux groupes, sans effets secondaires maternels et foetaux importants. Si on compare le fentanyl au sufentanil, les patientes qui recevaient du sufentanil ont rapportés pour la douleur des scores inférieurs et beaucoup moins de patientes ont eu besoin de bupivacaïne en supplément.

Stimulation of oxidative drug metabolism by parenteral refeeding of nutritionally depleted patients

To determine whether intravenous nutritional repletion can influence oxidative drug metabolizing capacity, antipyrine metabolism was studied in 6 malnourished patients on the second day of a 2-day baseline period and on the last day of two sequential, 8-day intravenous nutritional repletion periods. During the baseline period they received 5% dextrose, 440 kcal per day, intravenously. During the repletion periods they received 20 mg of nitrogen per kilocalorie of baseline resting energy expenditure and, in random order, dextrose to provide a total caloric intake of either 0.95 or 1.75 times baseline resting energy expenditure. There were no statistically significant differences between the high- and low-dextrose repletion regimens in their effects on antipyrine metabolism. Seven days of nutritional repletion resulted in a 42% decrease in mean half-life (range 12%-52%) and an 87% increase in mean metabolic clearance rate (range 29%-155%) for antipyrine. An additional 8 days of nutritional repletion resulted in no further change in these pharmacokinetic parameters.

Metabolism of desflurane and isoflurane to fluoride ion in surgical patients

The metabolism of isoflurane and the investigational volatile anaesthetic desflurane to fluoride ion was examined in 25 surgical patients. The patients were randomly assigned to four groups, to receive isoflurane or desflurane at either 0.65 MAC or 1.25 MAC. Anaesthesia was induced in all patients with thiopentone and midazolam and included nitrous oxide 60% in addition to the volatile agent. Blood was drawn before induction and at the end of the operation for determination of serum fluoride ion concentration. Plasma fluoride ion concentrations increased (+1.36 ± 0.93 μM, P < 0.01) in patients receiving isoflurane but were unchanged (− 0.13 ± 0.50 μM) in patients receiving desflurane. Metabolic release of fluoride ion is less with desflurane than with isoflurane during administration of the anaesthetics to surgical patients, and is unlikely to be of clinical significance.RésuméLe métabolisme de l’isoflurane et de l’anesthésique volatil sous investigation le desflurane en ion fluorure fut examiné chez 25 patients chirurgicaux. Les patients furent randomisés et divisés en quatre groupes afin de recevoir l’isoflurane ou le desflurane à soit 0,65 MAC ou 1,25 MAC. L’anesthésie fut induite chez tous les patients avec du thiopentone et du midazolam incluant du protoxyde d’azote 60% avec l’agent volatil. Du sang fut prélevé avant l’induction et à la fin de l’opération afin de déterminer la concentration d’ion fluorure sérique. Des concentrations des ions fluorure plasmatique augmentèrent (+ 1,36 ± 0,93 μM, P < 0,01) chez les patients recevant l’isoflurane mais furent inchangées (− 0,13 ± 0,50 μM) chez les patients recevant la desflurane. La libération métabolique de l’ion fluorure est moindre avec la desflurane que l’isoflurane durant l’administration de l’anesthésie chez les patients chirurgicaux et n’aura probablement pas de signification clinique.

Variability in Human Drug Metabolism

Individual differences in the response of people to a drug and variability in the response that occurs when patients are given a drug on several occasions are important problems in clinical pharmacology. Indeed, variability in the responsiveness of all living organisms to toxic chemicals has general importance in biology. Individuality in the responsiveness of humans to drugs and environmental chemicals is caused, in part, by differences in rates of chemical biotransformations in different individuals. In the present report, some studies on interindividual and intra-individual differences in the metabolism of foreign chemicals in humans and the effects of dietary factors on the metabolism of these substances in man are described.

THE REGULATION OF HUMAN DRUG METABOLISM BY NUTRITIONAL FACTORS

Publisher Summary This chapter summarizes the results of some early studies that were carried out on the regulation of drug oxidation rates by nutritional factors in man. A series of studies were initiated to examine the possibility that nutritional factors can significantly influence drug oxidation in man. The results of two such investigations are briefly described in the chapter. These studies focused on the influence of variations in the carbohydrate (CHO) and protein (PRO) composition of the diet on antipyrine and theophylline plasma elimination rates in normal subjects and on the effects, in similar individuals, of the manner of food preparation—specifically the charcoal broiling of meat—on the metabolic disposition of phenacetin. The results of the half-life studies of antipyrine and theophylline determined in test periods are described in the chapter. For each subject, there was a significant and sometimes marked decrease of antipyrine half-life in the shift from a home diet to a low CHO-high PRO diet.