Alice A. Holazo

Effects of Age, Gender and Oral Contraceptives on Intramuscular Midazolam Pharmacokinetics

The effects of age, gender and low‐dose (50 mcg or less) oral contraceptive steroids (OCS) on the pharmacokinetics of midazolam were evaluated following a single 7.5 mg intramuscular dose to five groups (8/group) of healthy volunteers consisting of young males, young females, elderly males, elderly females, and young female users of oral contraceptives. Blood samples were collected at specified times over a 24‐hour period, and plasma concentrations of midazolam and its 1‐hydroxymethyl metabolite were determined by a GC‐EC assay. Midazolam was rapidly absorbed following intramuscular administration to the different groups. Comparison of young men vs elderly men, young women vs elderly women, young men vs young women, elderly men vs elderly women, and young women OCS‐users vs young women non‐OCS users indicated no substantial differences in the pharmacokinetic profile of midazolam between groups except for the comparison between the young and elderly men groups. The rate of elimination of midazolam was significantly slower in the elderly males compared to the young men. The pharmacokinetic profile of 1‐hydroxymethyl midazolam paralleled that of the parent compound. This is to be expected since this metabolite exhibits formation rate‐limited kinetics. Except for one subject who reported hives and itching, considered to be remotely related to test drug, no other adverse experiences or laboratory abnormalities were reported.

Clinical bioavailability evaluation of a controlled release formulation of diazepam

A controlled release formulation of diazepam was compared to equal daily doses of the trade tablet under single day and steadystate conditions. Virtually no differences were found in the mean steadystate concentrations of diazepam or its metabolite, N-desmethyldiazepam, when the subjects received the 5 mg trade tablet three times daily or the 15 mg controlled release formulation once daily. Similarly, there was no difference in mean diazepam or N-desmethyldiazepam plasma concentrations when single doses of the controlled release formulation were given to fed or fasted volunteers. These data indicate that the controlled release formulation produces plasma concentrations of diazepam and N-desmethyldiazepam comparable to those achieved with the same daily dose of the trade product given three times daily, suggesting that these regimens can be used interchangeably.

Blood and salivary concentrations of sulfamethoxazole and trimethoprim in man

Saliva/blood and saliva/plasma concentration ratios were determined for sulfamethoxazole and trimethoprim following oral administration of cotrimoxazole to healthy human subjects. The mean experimentally determined saliva/plasma concentration ratios for sulfamethoxazole and trimethoprim were 0.0157 and 1.13, respectively. These values were shown to be in reasonable agreement with theoretical predictions. It was demonstrated that partitioning of drugs from saliva into the buccal must be considered in making theoretical predictions.

The influence of liver dysfunction on the pharmacokinetics of carprofen

The pharmacokinetics of the investigational agent carprofen were examined in 12 patients with liver dysfunction (hepatic cirrhosis) and in six normal volunteers following single 100‐mg oral administration of carprofen. In addition, three patients with acute hepatitis received a single 100‐mg dose during the acute phase of the disease, and two of these patients received the same dose after they had convalesced. The pharmacokinetic parameters and urinary excretion data did not differ significantly (P > 0.05) between patients with hepatic cirrhosis and healthy volunteers. The mean ± SD area under plasma concentration‐time curve and apparent oral plasma clearance values were 57.8 ± 11.7 μg × h/mL and 30.0 ± 6.3 mL/min, respectively, in patients and 52.4 ± 11.3 μg × h/mL and 33.1 ± 7.2 mh/min in normals. The respective harmonic mean elimination half‐lives were 10.5 and 9.4 hours. The 0–24 hour urinary recovery of intact drug and the glucuronide conjugate were 7.0 ± 4.9% and 28.9 ± 11.0%, respectively, in patients compared to 5.5 ± 7.1% and 20.1 ± 12.3% in normal subjects. The results of this study showed that liver dysfunction (hepatic cirrhosis) had no effect on the pharmacokinetic profile of carprofen. In the two patients with acute hepatitis who completed the study, the results suggest that the apparent oral clearance of carprofen may increase during the acute phase of the disease.

Verapamil Pharmacodynamics After Intravenous and Oral Dosing: Theoretic Consideration

Differences in the potency of intravenous (IV) and oral verapamil have recently been reported with the concentration‐response curve for PR‐interval prolongation being shifted further to the right following oral administration relative to IV administration. Using well‐established pharmacokinetic models, a theoretic basis for these observations is presented. Simultaneous curve fitting of the IV and oral verapamil plasma concentration and PR‐interval data to a single pharmacokinetic‐pharmacodynamic model allowed prediction of differences in the pharmacodynamic potency of verapamil as a function of the rate of drug administration. These data indicate that the rate of input of drug into the systemic circulation can influence the rate and extent of entry of drug into an effect compartment, which in turn can result in different plasma concentration‐response relationships.

Pharmacokinetic and Pharmacodynamic Modeling of Cibenzoline Plasma Concentrations and Antiarrhythmic Effect

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total‐data set, average‐data set, and grouped‐data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average‐data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.

(−)‐2‐Hydroxy‐N‐cyclopropylmethylmorphinan: Radioimmunoassay and pharmacokinetic profile

The pharmacokinetic profile of (−)‐2‐hydroxy‐N‐cyclopropylmethylmorphinan (HCMM), a narcotic antagonist and analgesic, has been evaulated in man following administration of 25 to 50 mg of the drug orally and 10 to 15 mg intramuscularly. A specific radioimmunoassay procedure was developed for the determination of HCMM in plasma and urine. The drug had a mean “apparent” elimination half‐life in plasma of about 11 hr following both routes of administration. A mean of 47% of the oral dose was excreted in the urine as unconjugated and conjugated HCMM and only 5% of the dose was excreted as intact HCMM. In one subject studied, the plasma levels of conjugated HCMM were as much as 5‐fold higher than the levels of un conjugated drug. Although there was considerable intersubject variability following both routes of administration, the overall pharmacokinetic parameters suggest that oral and intramuscular doses are bioequivalent.