Barry H. Dvorchik

Smoking‐induced changes in nicotine disposition: Application of a new HPLC assay for nicotine and its metabolites

A sensitive, rapid high‐pressure liquid chromatographic assay was developed to compare the disposition of an intravenous dose of l4C‐nicotine in normal, carefully matched smokers and nonsmokers. The elimination half‐lifes of nicotine and cotinine were shorter in smokers than in nonsmokers. Also consistent with an inductive effect of smoking was the increased nicotine elimination rate constant in smokers, but smoking induced more complex kinetic changes: nicotine volume of distribution was diminished in smokers, whereas nicotine clearance and area under the concentration‐time curve were unchanged. The presence of nicotine and its principal metabolites in a morning specimen of urine obtained from nonsmokers before 14C‐nicotine administration suggests ubiquitous, passive exposure to and absorption of chemicals present in cigarette smoke.

Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines.

Normal male volunteers on xanthine‐restricted diets had a plasma theobromine (TB) half‐life (t½) of6.1 ± 0.7 hr (mean ± SEM), a TB metabolic clearance rate (MCR) of 113.8 ± 6.8 mllmin (mean ± SEM). and an apparent volume of distribution (aVd) of 59.9 ± 7.8 L (mean ± SEM) after a single oral dose of6 mg/kg of TB. A two‐week period of dietary abstention from methylxanthines shortened the mean plasma TB t½ by 33% and increased the mean MCR ofTB by 59%; no change occurred in mean aVd of TB. In another experiment, normal male volunteers received the same oral dose of TB for each of five consecutive days. The mean plasma TB t½ measured immediately after the last TB dose was prolonged by almost two‐thirds, while the mean aVd increased 23%. Although the mean plasma TB t½ measured four days after this last TB dose was the same as that measured after a single oral dose, the mean MCR of TB increased by 34%, but this change was balanced by increased mean aVd of 35%. These results suggest that immediately after five daily doses ofTB, an impairment ofTB clearance occurs that is reversible by four days of dietary abstention from methylxanthines.

High levels of methylxanthines in chocolate do not alter theobromine disposition

Theobromine disposition was measured twice in 12 normal men, once after 14 days of abstention from all methylxanthines and once after 1 week of theobromine (6 mg/kg/day) in the form of dark chocolate. Mean theobromine t½, apparent volume of distribution, and clearance after abstinence from all methylxanthines were 10.0 hours, 0.76 L/kg, and 0.88 ml/min/kg. High daily doses of chocolate for 1 week did not change these values. After subjects abstained from methylxanthines, urinary radioactivity over 72 hours after a single, oral dose of [8‐14C]theobromine consisted of 42% 7‐methylxanthine, 20% 3‐methylxanthine, 18% theobromine, 10% 7‐methyluric acid, and 10% 6‐amino‐5[N methyl‐formylamino]‐1‐methyluracil. A week of daily theobromine consumption in the form of dark chocolate also did not alter this urinary profile of theobromine and its metabolites. Although these results might appear to differ from other reports of inhibition of theobromine elimination after five consecutive daily doses of theobromine in aqueous suspensions, both the rate and extent of absorption of theobromine in chocolate were less then that of theobromine in solution. Relative bioavailability of theobromine in chocolate was 80% that of theobromine in solution. This reinforces the fundamental principle that both the metabolic and the therapeutic consequences of a particular chemical can differ when that chemical is given in the pure compared with the dietary form.

Significance of error associated with use of the one‐compartment formula to calculate clearance of thirty‐eight drugs

A survey of the literature was performed to gather information on the magnitude of the error introduced into calculating drug clearance by using a one‐compartment formula for drugs whose disposition follows multicompartment kinetics. Sufficient data to permit quantitation of this error were found for 38 drugs. The magnitude of the error varied widely depending on the initial distribution of the particular drug. Antipyrine and such commonly used drugs as amobarbital, chlordiazepoxide, nortriptyline, pentobarbital, phenytoin, sulfisoxazole, theophylline, tolbutamide, and warfarin had errors of 8% or less, thereby permitting utilization of the one‐compartment formula for determination of drug clearances without much loss of accuracy. However, 22 drugs exhibited errors ranging from 12% to 196%; for these drugs, the one‐compartment formula introduced considerable inaccuracy. The errors for diazepam, meperidine, and propranolol, when administered to patients with hepatic cirrhosis or to hypertensive patients, were 4%, 5%, and 6%, respectively, whereas in normal subjects the errors were 18%, 14%, and 2/%. Thus, the clinical status of the subject may influence the choice of the model used. On the basis of these data we conclude that for many commonly used drugs the one‐compartment formula is acceptable for determining drug clearance, loading dose, or maintenance dose.

Gas chromatographic determination of cocaine in whole blood and plasma using a nitrogen-sensitive flame ionization detector

A procedure is described for the determination of as little as 20 ng of cocaine from 1 ml of whole blood or plasma. Methods are also given for the storage of whole blood or plasma containing cocaine as well as for whole blood or plasma extracts. Blood levels in patients receiving intranasal cocaine for topical anesthesia while undergoing rhinoplasty are also presented.

Influence of Different Forms of Tobacco Intake on Nicotine Elimination in Man

In each of three separate experiments mean plasma nicotine t1/2 beta was slightly, but statistically significantly, shorter in habituated compared to naive cigarette smokers. Two of these experiments involved nicotine administration by smoking a cigarette containing a standardized amount of nicotine, whereas in the third experiment nicotine was injected intravenously as a single tracer dose of 14C-nicotine. In contrast to cigarette smokers, naive and habituated snuff dippers had similar mean plasma nicotine t1/2 beta. Habituated pipe smokers tended to have very slightly, but not statistically significantly, shorter plasma nicotine t1/2 beta S than naive pipe smokers. These distinctions are related to special features that characterize each form of tobacco intake.

Dietary patterns and diurnal variations in aminopyrine disposition

In healthy, nonmedicated male subjects, patterns of eating and fasting determined diurnal variations in aminopyrine disposition. Under dietary conditions used in our laboratory to study temporal variation in the disposition of aminopyrine (a 12‐hr fast preceding 8 A.M. dose and a 5 P.M. meal before 8 P.M. drug dosing) there was a mean diurnal variation of 33% in saliva aminopyrine half‐life (t½) and of 46% in apparent volume of distribution (aVd) with shorter t½ and lower aVd at 8 A.M. Mean metabolic clearance rate (Cl) was unchanged. Fasting for 32 and 44 hr before aminopyrine at 8 A.M. and 8 P.M. ablated this temporal variation in aminopyrine t½ and aVd. Reversal of eating times (a 12‐hr fast before the 8 P.M. aminopyrine dose and a 5 A.M. meal before the 8 A.M. dose) reversed the direction of the diurnal variation of aminopyrine t½ and aVd so that aminopyrine t½ and aVd were larger at 8 A.M. but fasting for 32 or 44 hr did not alter the normal circadian rhythms of plasma 11‐hydroxycorticoids identified in our subjects at 8 A.M. and 8 P.M. Plasma protein binding of aminopyrine, determined at 8 A.M. after a 12‐hr fast (29.8%), was higher than at 8 P.M. (23.3%, p < 0.05). Aminopyrine protein binding rose to 38.1% and 32.9% after a fast of 32 and 44 hr. Mean bioavailability and area under the curve of aminopyrine determined in plasma at 8 A.M. and 8 P.M. showed no diurnal change. As in saliva, aminopyrine concentrations in plasma revealed that mean aminopyrine t½ was 34% longer, mean aminopyrine aVd 33% larger, but mean aminopyrine Cl the same at 8 P.M. as at 8 A.M. These results suggest that meals decrease protein binding of aminopyrine, leading to increased aminopyrine aVd and t½, possibly due to increased tissue uptake of aminopyrine. Aminopyrine plasma concentrations after oral doses of 2, 4, and 8 mg/kg at 1‐wk intervals to each of six normal male subjects revealed dose dependence of aminopyrine t½ and hepatic first‐pass effect.

Cocaine concentrations in the blood during rhinoplasty.

After applying 5% or 10% cocaine to the nasal mucosa, blood concentration were measured in 9 patients undergoing rhinoplasty and in 6 unoperated controls. The concentrations in the unoperated persons were lower than in those undergoing rhinoplasty, and lower concentrations were found after 5% solutions in both groups than in those exposed to 10% solutions. There was no correlation between the strength of the solution used and the degree of bleeding or the success of the anesthesia. One patient developed symptoms of toxicity within two minutes of a 5% cocaine application to his nasal mucosa. The cocaine concentrations in his blood were the highest seen in our studies, and we cannot explain this.

Gas chromatographic method for the microdetermination of barbiturates in blood using a nitrogen-selective flame ionization detector

A rapid, quantitative gas-liquid chromatographic method for the simultaneous determination of as little as 10 ng of unmodified barbital, pentobarbital, secobarbital, and hexobarbital from whole blood is described. The method involves one extraction from whole blood into chloroform with subsequent injection into a gas chromatograph equipped with a nitrogen-sensitive flame ionization detector. This method has the advantages of small sample size high specificity, sensitivity, and rapidity.

Drug Metabolism by the Fetal Stump-Tailed Monkey (Macaca arctoides)

Sensitive radiometric assays were adapted to study the development and kinetics of meperidine and methadone N-demethylation and morphine glucuronidation by microsomes isolated from livers of fetal stump-tailed macaques (Macaca arctoides). Times in development selected for study were midterm, three-quarter term, near term and newborn (0.5 h and 14 days). With appropriate attention to keeping blanks low, hepatic drug metabolism was demonstrable as early as midterm. Vmax for the N-demethylation reactions (nmole product/10 min/mg microsomal protein) increased throughout gestation, whereas the apparent Kms remained constant. With respect to morphine glucuronidation, all kinetic parameters remained constant throughout the last half of gestation.