David P. Benziger

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.

Subchronic Oral and Intravenous (iv) Safety Evaluation and Pharmacokinetics in Rats and Dogs of Ipazilide Fumarate (Win 54, 177-4), an Antiarrhythmic Agent

Ipazilide fumarate (Win 54, 177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20-320 mg/kg oral and 1.25-10 mg/kg iv) and 14 and 28 days in beagle dogs (3-30 mg/kg oral and 2.5-20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (tmax less than or equal to 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., Cmax 4-5 micrograms/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of a novel steroidal androgen receptor antagonist (Win 49596) in human plasma using solid-phase extraction and high-performance liquid chromatography with ultraviolet detection.

A rapid, sensitive and selective method was developed for the determination of a novel steroidal androgen receptor antagonist (Win 49596, I) in human plasma. The procedure involved extraction from plasma using a solid-phase phenyl support and elution directly onto a reversed-phase C8 column using a mobile phase consisting of 0.2 mol/l sodium acetate buffer at pH 7-acetonitrile (45:55, v/v). Drug was monitored by ultraviolet detection at a wavelength of 238 nm. Linear responses were observed for standards over the range 0.01-5.0 micrograms/ml. The minimum quantifiable level was 0.02 microgram/ml, using a 0.5-ml plasma sample. The precision was 5.5% and the accuracy ranged from -9.4% to 0.23%. The analytical method has been used to quantify I in plasma from dogs and rats and is projected for use with human plasma from clinical trials.

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.