dextromethorphan and cycloguanil

Honey is a common food supplement but not many studies have studied honey and drug interaction. This study investigates the influence of 7 days of honey administration on the activity of CYP3A4, CYP2D6 and CYP2C19 drug-metabolizing enzymes in healthy volunteers by using appropriate biomarker and probe drugs. A within-group pharmacokinetic study was done in 12 healthy volunteers. Urine samples (0-8 hr) were collected after administration of 30 mg of oral dextromethorphan (probe drug for CYP2D6) for analysis of dextromethorphan and dextrorphan. A plasma sample (4 hr) was collected after administration of 200 mg of oral proguanil (probe drug for CYP2C19) for the analysis of proguanil and cycloguanil. Urine samples (0-24 hr) were collected for the analysis of 6beta-hydroxycortisol (biomarker for CYP3A4). The volunteers were administered honey for 7 days. Subsequently blood and urine samples were collected after drug dosing as before. These samples were analysed for drug and metabolite concentrations in urine and plasma using high performance liquid chromatography method. Seven days of honey administration resulted in statistically significant increase in 24-hr urinary excretion of 6beta-hydroxycortisol. However, the metabolic ratios of dextromethorphan and proguanil were not significantly altered after 7 days of honey administration. Honey obtained from Western Ghats of southern India may induce CYP3A4 enzyme activity but not CYP2D6 and CYP2C19 enzyme activities.

Topics: Administration, Oral; Adult; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dextromethorphan; Dextrorphan; Honey; Humans; Hydrocortisone; India; Male; Mixed Function Oxygenases; Proguanil; Triazines

It has been suggested recently that the bioactivation of chloroguanide hydrochloride (proguanil) to its active antimalarial metabolite cycloguanil cosegregates with the genetically determined polymorphism of mephenytoin hydroxylation. We determined the chloroguanide to cycloguanil ratio in urine after oral administration of a single dose of 200 mg proguanil either alone or together with 100 mg racemic mephenytoin or 40 mg dextromethorphan in a randomized crossover study performed in 24 healthy subjects. The mephenytoin hydroxylation index was also determined after administration of 100 mg racemic mephenytoin either alone or together with 200 mg proguanil. Two subjects were poor metabolizers and one subject was an intermediate metabolizer of mephenytoin. These three subjects had chloroguanide to cycloguanil ratios of more than 50. The 21 subjects with the extensive metabolizer phenotype for mephenytoin hydroxylation had chloroguanide to cycloguanil ratios of less than 10. The chloroguanide to cycloguanil ratio was not significantly altered by mephenytoin or dextromethorphan coadministration. The trend toward a correlation between chloroguanide/cycloguanil ratio and log mephenytoin hydroxylation index did not reach statistical significance. Inclusion of the dextromethorphan metabolic ratio into the model did not improve the relationship. These findings confirm that the bioactivation of chloroguanide to cycloguanil cosegregates with the genetically determined activity of the CYP2C family. However, the chloroguanide to cycloguanil ratio and the mephenytoin hydroxylation index do not similarly reflect the variable activity of CYP2C.

Topics: Adult; Aryl Hydrocarbon Hydroxylases; Biotransformation; Cytochrome P-450 Enzyme System; Dextromethorphan; Female; Humans; Hydroxylation; Male; Mephenytoin; Polymorphism, Genetic; Prodrugs; Proguanil; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Triazines

To investigate the relationship between proguanil metabolic ratio (MR, proguanil/cycloguanil) and CYP2C19 genotype in a Caucasian population.. Ninety-nine Caucasians (age range: 18-55 years, 54 female, 45 male) were genotyped for CYP2C19 and phenotyped for proguanil oxidation by collecting urine for 8 h after taking 100 mg proguanil hydrochloride. Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping.. The three (3%) individuals who were homozygous for CYP2C19*2 (*2/*2) had the highest proguanil MRs (range: 8.0-134.6). Seventy-three (74%) individuals were homozygous for the wild-type allele (*1/*1) and 23 (23%) were heterozygous (*1/*2). The *1/*1 individuals had lower MRs (median=1.4, range: 0.23-5.9, P=0.003, Mann-Whitney U-test) than the *1/*2 subjects (median=2.5, range: 0.88-7.3).. A CYP2C19 gene-dose effect for proguanil oxidation to cycloguanil was observed, confirming a role for CYP2C19 in cycloguanil formation in vivo. However, there was substantial overlap of proguanil MRs in subjects of different CYP2C19 genotypes, due possibly to variability in the activity of other enzymes contributing to the formation of cycloguanil.

Topics: Adolescent; Adult; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Dextromethorphan; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Mutation; Proguanil; Statistics as Topic; Triazines; White People