Jerome Edelson

Absorption from the Vagina

Methods and results are reviewed of research on the permeability of the vagina to a wide variety of compounds including steroids, prostaglandins (PGs), antimicrobials, proteins, antigens, and hormones, nonoxynol-9, methadone, and inorganic compounds. Although the literature indicates that the vagina is capable of absorbing a wide variety of organic and inorganic compounds, quantitative data on the extent of absorption are often lacking. Most steroids were readily absorbed and their bioavailability after intravaginal instillation was greater than after oral administration because of a reduced first-pass effect. Natural and synthetic PGs were absorbed; the extent of absorption ranged from 10-43% of the dose. Penicillin and sulfanilamide exhibited extremely variable absorption from the vagina. In most women neither econazole, miconazole, nor clotrimazole were effectively absorbed. In 1943 it was demonstrated that proteins could be absorbed from the vagina. Data on human absorption of nonoxynol-9 are indirect but are consistent with absorption. Methadone, povidone-iodine, and potassium permanganate have also been shown to be absorbed through the vagina. The stage of the reproductive cycle may alter the extent of vaginal absorption, but this has been clearly demonstrated for only 1 substance in the rat.

A radioimmumoassay for danazol (17α-Pregna-2,4-Dien-20-Yno[2,3-d]Isoxazol-17-OL)

A method is described for the radioimmunoassay of circulating levels of the pituitary inhibiting agent, danazol. An antigen for danazol was prepared by reacting a 17-carboxy-methyloxime derivative of danazol with bovine serum albumin. By immunizing rabbits with this antigen, antiserum was generated which shows excellent specificity for danazol relative to its known metabolites as well as to many natural steroids. A radioimmunoassay was developed, without using separation or extraction techniques, involving competition for the antiserum between danazol in plasma and 14C-danazol. This assay has been successfully used to measure danazol in a series of normal human subjects receiving the drug at either 100 or 200 mg b.i.d. for 2 weeks. A significant relationship was seen between dosage of danazol and plasma concentrations.

Dose proportionality of amrinone

Arminone was given to 18 healthy subjects in doses of 75, 150, and 225 mg in a randomized crossover design. Plasma levels were shown to rise in proportion to dose. The mean plasma AUC, extrapolated to infinite time, was determined for each dose level; the values obtained were 4, 8.18, and 12.35 μg · hr/ml for the 75‐, 150‐, and 225‐mg doses. Mean maximum observed plasma concentrations were 1.03, 1.74, and 2.58 μg/ml. At higher doses the extrapolated AUC is more variable, but it is linear over the range of 0.73 to 3.81 mg/kg. The apparent first‐order terminal elimination rate is not dose dependent and corresponds to a t½ of 3.85 hr.

High-performance liquid chromatographic determination of plasma and urinary 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3,7-dicarboxylic acid.

A high-performance liquid chromatographic method for the analysis of 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3,7-dicarboxylic acid (I) in plasma and urine is described. A statistical evaluation of the assay technique has shown acceptable accuracy and precision at concentrations as high as 2.0 microgram/ml of plasma or 29.0 microgram/ml of urine for samples augmented with 1. As little as 0.08 microgram/ml of I in plasma or 0.42 microgram/ml of I in urine were quantitatively determined. The mean relative error for the assay of unknown concentrations of I in plasma and urine was +/- 8% and +/- 3%, respectively. This method was used for the analysis of I in the plasma and urine of rhesus monkeys following oral administration of 200 mg/kg of nalidixic acid.

The analysis of arildone in plasma, urine and feces by gas—liquid chromatography with electron-capture detection

The analysis of arildone in plasma, urine and feces by gas--liquid chromatography with electron-capture detection is described. O-(2,3,4,5,6-Pentafluorobenzyl)hydroxylamine is the derivatizing agent for the plasma and urine analysis; 3-nitrophenylhydrazine is utilized for fecal analysis. The mean (+/- S.E.) minimum quantifiable level of arildone was 1.4 (+/- .02) ng/ml in urine, 6.4 (+/- 0.1) ng/ml in plasma, and 12.6 (+/- 1.0) ng/g in feces. The chromatographic response was linear in the range of 0 and 10--120 ng/ml for plasma, 0 and 2.5--20 ng/ml for urine and 0 and 25-250 ng/g for feces. The estimated overall precision of the assay was 5.5%, 64% and 8.9% in urine, plasma and feces, respectively.

High-performance liquid chromatographic analysis of roxoxacin and its N-oxide metabolite in plasma and urine

Abstract A high-pressure liquid chromatographic methoc for the analysis of rosoxacin and its pyridyl N-oxide metabolite in plasma and urine extracts is described. A statistical evaluation of the assay data has shown acceptable accuracy and precision for 0.5 to 25 μg of rosoxacin or the metabolite per ml of plasma and for 2.5 to 60 μg/ml of either compound in urine. The minimum quantifiable level for rosoxacin was 0.13 μg/ml in plasma and 0.64 μg/ml in urine; for the metabolite in plasma and urine, the corresponding values were 0.21 and 0.60 μg/ml, respectively. The method was applied to plasma and urine from three dogs medicated orally with 5 mg/kg of rosoxacin. The pharmacokinetic parameters calculated for rosoxacin were: plasma half-life, 1.9 h; plasma clearance, 65 ml/min; volume of distribution, 11.31. The average total urinary excretion of resoxacin as free and conjugated rosoxacin and its free N-oxide was 7.7 ± 0.2% over the 48-h collection period.

Chapter 33. Drug Metabolism

Publisher Summary The drug metabolism chemist is usually concerned with only the three major reaction pathways; these are oxidative, conjugative and hydrolytic processes. The vagaries of mother nature determine the sequence and combinations of these three reactions that are responsible for the vast majority of biotransformations involving drug substances. These biological reactions, in conjunction with the kinetics of the processes involved and the development of the technology needed to measure these products, have expanded the literature of drug metabolism at an increasing rate. The relationship between the toxicity and drug metabolism is of continuing interest. The chapter discusses pharmacokinetics. It here states about the alternative methods for estimating the pharmacokinetic parameters based on direct linear plotting, linear system analysis, and zero-order absorption with first-order elimination processes. There are new methods to evaluate the bioequivalence of drugs with changing half-lives and to assess the acceptability of two comparable drug formulation . The effects of antacids on the bioavailability of diflunisal and theophylline have been discussed in the chapter. Urinary pH dramatically affects the excretion of both meperidine and its metabolite, normeperidine, but has a negligible effect on the blood concentration. Study on some other drugs mentioned here, how the dose affects the body and how fast the drug gets absorbed in the system, the residual amount and the rate of the elimination of residue. The chapter discusses the analytical methods to the study of drug metabolism. Drug disposition, metabolite formation, implementation of their toxicity, and antitoxicity measures are explained in the chapter with examples.

Determination of fezolamine and its desmethyl metabolite in human plasma and urine by high-performance liquid chromatography : Intravenous pharmacokinetics in the beagle hound

Sensitive and selective high-performance liquid chromatographic methods for the quantitation of the experimental antidepressant fezolamine and its desmethyl metabolite in plasma and urine have been developed. Both assays are linear between 0 and 500 ng/ml in both plasma and urine and have calculated minimum quantifiable levels of less than 10 ng/ml. Statistical evaluation of analytical parameters under single-blind conditions demonstrated an overall precision within +/- 4% of nominal for both compounds in either biological medium. The overall accuracies of the assays were within +/- 5% of nominal values in urine and +/- 10% of nominal values in plasma. Following intravenous administration of fezolamine fumarate to beagle hounds, a biexponential decline in drug plasma levels was observed with the first phase having a half-life of about 11 min and the second phase about 2.6 h. Peak plasma levels of the metabolite were observed at 2 h. Recovery of the parent drug in urine was less than 5% of the administered dose and less than 1% for the desmethyl metabolite.

Chapter 29. Drug Metabolism

Publisher Summary This chapter illustrates drug metabolism that is rapidly proliferating because of the factors that include: rapid advances in methodology, demands of drug regulatory agencies, and unraveling of the mechanisms involved. The use of immunoassays as an analytical method for drugs was in use previously. Researches focused on the clinical pharmacokinetic aspects of diuretics, antiarrhythmic agents, drug use in childbirth and in the postoperative period, and on extracorporeal hemoperfusion techniques. The pharmacokinetics of benzodiazepines has been intensively studied with regard to the effects of subjects age and sex. The elderly had a mean eleven hour prolongation of the half-life of nitrazepam, a mean prolongation of forty-eight hours for diazepam, and no prolongation with lorazepam. Several novel methods for determining the pharmacokinetic parameters have been reported. By using only the area under the plasma concentration versus time curve, the maximum plasma concentration and the time to the maximum concentration, it is possible to determine the equivalence of the apparent first-order rate constants for the absorption and elimination in a one-compartment body model. The metabolism of timolol was compared in animals and man. The oxidative opening of the morpholine ring and the oxidation of the oxypropanolamine side chain appear to be mutually exclusive pathways, the former being of greater importance in rodents and man and the latter in dog. In contrast, 4-ethoxy-2-methyl-5-morpholino-3-(2H)-pyridazinone was metabolized mainly by opening the morpholine ring in mice, rats, rabbits, dogs, and monkeys.

Disposition of a Series of Tetrahydrocarbazoles

Cyclindole was extensively metabolized and eliminated primarily via the kidneys from most laboratory animals and man. Only in the dog was cyclindole a major urinary component. Cyclindole was metabolized by N-demethylation and/or hydroxylation. In studies utilizing radiolabeled drug, the primary urinary component was polar material which probably resulted from conjugation of the hydroxylated products. When desmethylcyclindole was administered to rats and dogs, large amounts of unchanged drug were administered to rats and dogs, large amounts of unchanged drug were recovered in the urine; there was no 3-aminotetrahydrocarbazole present. Significant amounts of urinary radioactivity were thought to represent hydroxylated and/or conjugated products. When 7-hydroxycyclindole was administered to dogs, only free parent drug was recovered from the urine; there was no evidence for N-demethylation. Flucindole, the 6,8-difluoro analog of cyclindole was metabolized by dog and man via N-demethylation with the formyl derivative being a probable intermediate in this reaction; both products were found in the urine. No didesmethyl metabolite was detected. In contrast to cyclindole, the N-oxide of flucindole was found in urine from both species. The route of elimination of oxarbazole and its metabolites was species specific: urinary excretion was 96.5, 38.7, 24.5, and 2.0% for the guinea pig, monkey, rat, and dog, respectively. The major urinary metabolite was O-demethyl oxarbazole; this metabolite was conjugated in all species except the guinea pig. The dog and monkey excreted small quantities of conjugated N-debenzoylated oxarbazole in urine. The profound changes in pharmacological activity that result from relatively small chemical modifications of the tetrahydrocarbazole nucleus make it likely that many further investigations of this class of compounds will be undertaken in the future.