Prediction of phenotype for dextromethorphan O-demethylation by using polymerase chain reaction in healthy volunteers.

The polymorphism of dextromethorphan (CAS 125-71-3) metabolism is dependent on hepatic cytochrom P4502D6 (CYP2D6) activity. The relationship between the CYP2D6 genotype and the dextromethorphan phenotype was studied in 83 healthy unrelated subjects. Genotype was determined by allele-specific polymerase chain reaction (PCR). Phenotyping was performed by administration of 25 mg dextromethorphan hydrobromide and determination of the urinary metabolic ratio of dextromethorphan and its O-demethylated metabolite dextrorphan (DEM/DOR). Six subjects (7.2%) were homozygous for mutant alleles (95% confidence interval 2.7%-14.7%), 18 subjects (22%) were heterozygous carriers, and 59 were homozygous for the wild-type allele. Six subjects were classified as poor metabolizers (PM) of dextromethorphan, 77 as extensive metabolizers (EM). Genotyping correctly predicted all PMs and EMs. The CYP2D6-B mutation was most frequently found, being present in 83% of PM and 8% of EM alleles. Heterozygous EMs (22% of the total population studied) were significantly underrepresented compared to the expected genotype frequency of 31% (p < 0.05). The extensive metabolizers who were heterozygous for the wild-type allele had a significantly higher metabolic ratio, compared to the homozygous EMs (log10DEM/DOR [95% = -1.99 [(-2.30)-(-1.69)] vs. -2.55 [(-2.67)-(-2.43)]; p < 0.001), indicating a gene-dose effect for CYP2D6.

The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of omeprazole.

AIDS patients may have achlorhydria, a condition that could result in drug malabsorption, especially of antifungals. The effect of a reduction in the production of gastric acid on the pharmacokinetics of the antimycotic fluconazole after a single 100 mg dose was investigated in a randomized two-way crossover study with 12 healthy volunteers. Gastric acid production was reduced by pretreatment with 20 mg omeprazole/day over a period of 7 days; pH and gastric emptying times were measured by a radiotelemetering pH capsule. Omeprazole pretreatment significantly raised the median gastric pH (from pH 1.1 to pH 4.7, p < 0.0001), but had no significant influence on gastric emptying time of the pH capsule (median = 4.3 vs 4.9 hours). The pharmacokinetics of fluconazole were unchanged; plasma parameters were Cmax = 2.04 micrograms/ml, tmax = 4.08 h and AUC = 98.91 h micrograms/ml after the omeprazole treatment, compared to 2.06 microliters/ml, 3.92 hours and 97.29 h micrograms/ml, respectively. The median bioavailability ratio of fluconazole before and after omeprazole treatment was 1.00. It is inferred that there is no interference of omeprazole with the plasma pharmacokinetics of fluconazole. The findings suggest that changes in gastric pH, as in patients with AIDS or those being treated with anti-ulcer drugs, should not influence the pharmacokinetics of fluconazole.

[Biopharmaceutic properties of slow-release codeine phosphate. Drug release from ion exchangers in vitro and in vivo]. / Biopharmazeutische Eigenschaften von retardiertem Codeinphosphat. Untersuchung der Wirkstoff-Freisetzung eines Ionenaustauschers in vitro und in vivo.

The release of bound codeine (CAS 76-57-3) from a cation exchanger was examined in vitro by the flow-through method and in vivo by measuring the plasma concentrations of codeine after administration of slow-release (Codipront Retard) and standard non-retarded drops. Both sets of results show that codeine release from the ion exchanger is protracted and continuous. Relative to the standard formulation the slow-release codeine drops give a lower maximal plasma concentration (Cmax), a delayed time of maximal concentration (tmax), slower absorption (t0.5) and protracted plasma levels. The in vitro and in vivo results were in good agreement.

Bioavailability of fluconazole in the skin after oral medication.

Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 micrograms ml-1, sweat 4.58 micrograms ml-1, dermis-epidermis (without stratum corneum) 2.77 micrograms g-1 and stratum corneum 73 micrograms g-1. Thus, 4 h after the last dose the antimycotic attains a 40-fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 micrograms g-1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 micrograms g-1. Even 4-5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2-3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses.

Pharmacokinetics and tolerance of fluconazole suppositories in healthy volunteers.

Fluconazole (Diflucan, CAS 86386-73-4) suppositories offer a novel way to administer this systemically active antimycotic. The pharmacokinetics and toleration of this new formulation have now been examined in healthy adult volunteers. In crossover experiments the bioequivalence was demonstrated for 200 mg suppositories and 200 mg capsules, and for 25 mg suppositories and 25 mg fluconazole in an oral suspension. The mean bioavailability of the 200 mg suppository relative to the capsule was about 93%. The mean bioavailability of the 25 mg suppository relative to the oral suspension was 107%. Absorption of fluconazole after administration of the suppositories was, however, somewhat slower than after oral ingestion of the capsule or suspension. The pharmacokinetic parameters of the 200 mg and 25 mg suppositories suggest that the kinetics of rectally administered fluconazole are linear with dosage. Daily administration of the 200 mg suppository gives a continuous increase in the mean fluconazole plasma concentration, until steady-state is reached on about the 5th day. The systemic and local toleration of the fluconazole suppositories was good.

Relative bio-availability of sultamicillin in healthy volunteers following administration of two tablet formulations.

The pharmacokinetics of both ampicillin and sulbactam obtained from a balanced, open two-way crossover study in 20 normal adult volunteers receiving a single 375 mg oral tablet of sultamicillin administered as two different formulations--the original product (Duocid) and a generic formulation that is commercially available in Turkey--were compared. Pharmacokinetic parameters for the two formulations and for both ampicillin and sulbactam were tested for bio-equivalence by the two one-sided Student's t-test (80-120% range; P < 0.1). Area under concentration--time curves and maximum concentrations for both components were found to be non-equivalent for the two formulations, the generic formulation having consistently lower mean values. The results were consistent with studies of the in vitro release of sultamicillin from the two tablets. It is concluded that the generic formulation is pharmacokinetically inferior to the original product.

Mechanism of azithromycin uptake in human polymorphonuclear leucocytes.

The new antibiotic azithromycin (CP-62.993) is enriched in human polymorphonuclear leucocytes by up to 300-fold the extra-cellular concentrations. To approach an understanding of the underlying mechanism of this unique behavior of azithromycin, some characteristics of the uptake process were investigated in vitro. The speed of the uptake in human polymorphonuclear leucocytes was found to be independent of the extracellular starting concentrations of azithromycin. There was no indication of saturation up to extracellular concentrations of 100 micrograms/ml. The uptake was largely determined by incubation temperatures. At 4 degrees C no penetration into the cells could be observed. The activation energy of azithromycin uptake came to 144 kJ mol-1, twice the value of erythromycin uptake. The presence of various inhibitors of cell metabolism did not change the intracellular accumulation compared to control, nor did the presence of some agents which interfere with certain transport channels. These findings suggest that passive diffusion is an essential mechanism of azithromycin transport through the phagocyte membrane, while active transport is less important. The high cellular enrichment of azithromycin and the relatively high activation energy of the uptake process could be explained by accumulation of the drug in phagocytic lysosomes and this would also be in keeping with pH partition considerations.

Relationship between frequency of sexual intercourse and urinary tract infections in young women.

We compared personal and sexual behavior of a group of 32 young adult women who had a culture proven urinary tract infection (UTI) and a group of 28 women who had no urinary symptoms. All women were sexually active, and the two groups were similar for age, race, marital status, history of previous pregnancy, and use of oral contraceptives. The major finding was an increase in the frequency of sexual intercourse by the study group immediately before the onset of symptoms. No group differences were found for manner of perineal hygiene, frequency of urination, frequency of refraining from voiding after the initial urge, and frequency of urinating after coitus. We conclude that an increase in sexual intercourse may be one of the factors involved in the development of a symptomatic UTI in young women.

Sexual behavior and urinary tract infection.

A study to identify factors which put young, sexually active women at risk to develop a urinary tract infection (UTI) was done. Reported here are differences in sexual behaviors in the study and control groups. All subjects were currently sexually active. Study subjects had a urine culture of greater than 10(5) single pathogen species. Control subjects were healthy women seeking preventive health care services. Both groups completed a self-administered questionnaire consisting of demographic data, past personal and family history, health status, habits of daily living and sexual activity and behaviors. Data analysis results showed that women who develop a UTI were more sexually active than their counterparts who did not. The data also indicate that increased coital activity preceded a UTI, and that the female superior position was used more frequently. Other coital activities and related sexual behaviors tested were not significantly different in the two groups, nor were they associated with the onset of a urinary tract infection. The results of this pilot study indicate a potential need to review the content of current preventive health teaching about UTIs. The validity of these findings must be further investigated before a conclusive statement or recommendations can be made.