Metabolism Of Proguanil Research Articles

Physiologically based pharmacokinetic model analysis of the inhibitory effect of vonoprazan on the metabolic activation of proguanil

We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms other than metabolic inhibition may be involved.

A Review of Pharmacogenetics of Antimalarials and Associated Clinical Implications.

Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.

Phenotyping and genotyping of CYP2C19 using comparative metabolism of proguanil in sickle-cell disease patients and healthy controls in Nigeria.

Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle‐cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported. One hundred seventy‐seven unrelated subjects comprising 131 SCD patients and 46 non‐SCD volunteers were phenotyped. This was carried out by collecting pooled urine samples over 8 h following PG administration. Proguanil and its major CYP2C19‐dependent metabolites were measured by high‐performance liquid chromatography. Metabolic ratios (MRs) were computed and employed in classifying subjects into poor or extensive metabolizers. Among SCD group, 130 (99.2%) were extensive metabolizers (EMs) and 1 (0.8%) was poor metabolizer (PM) of PG, while 95.7 and 4.3% non‐SCDs were EMs and PMs, respectively. MRs ranged from 0.02 to 8.70 for SCD EMs and from 0.22 to 8.33 for non‐SCD EMs. Two non‐SCDs with MRs of 18.18 and 25.76 and the SCD with MR of 16.77 regarded as PMs had earlier been genotyped as CYP2C19*2/*2. Poor metabolizers of proguanil in SCD patients are reported for the first time. Regardless of clinical significance, a difference in metabolic disposition of proguanil and CYP2C19 by SCDs and non‐SCDs was established.

Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400 mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases ( p < 0.05) in C max, T max, AUC T and elimination half-life ( T 1/2 β ) of proguanil compared with values for proguanil alone [ C max: 2.55 ± 0.24 mg/l vs 3.75 ± 0.48 mg/l; T max: 2.80 ± 0.99 h vs 4.80 ± 0.99 h; AUC T: 45.58 ± 12.75 mg h/l vs 97.00 ± 23.33 mg h/l; T 1/2 β : 16.50 ± 4.55 h vs 23.24 ± 4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease ( p < 0.05) in C max and AUC of the metabolite. These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels.

Polymorphic oxidative metabolism of proguanil in a Nigerian population.

The genetic polymorphic metabolic oxidation of proguanil was investigated in 126 healthy, unrelated Nigerian subjects as an indication of the phenotypic status of CYP2C19 in Nigerians. The proguanil oxidation capacity was determined using the 8-h urinary metabolic ratio of the parent drug and its metabolite (cycloguanil) after a single oral dose of 200 mg proguanil. The frequency distribution of the proguanil metabolic ratio ranged from 0.01 to 39.64 with a median of 1.38 in the 126 Nigerians. On the basis of the antimode value of 10 for the proguanil/cycloguanil ratio, the prevalence of poor metabolisers in this Nigerian population was estimated to be 4.8% (6 of 126), which is very similar to that of S-mephenytoin (4.3%) found in a previous study in Nigerians. The data also demonstrated enormous inter-individual differences in the urinary proguanil/cycloguanil ratios with poor metabolisers excreting, on average, only about 8% of the quantity of cycloguanil excreted by extensive metabolisers. The incidence of phenotypically poor metabolisers of proguanil in this Nigerian population is similar to those reported for Caucasian and other African populations but is much lower than those reported for Orientals. The study further supports previous studies that proguanil can be used as an alternative probe to phenotype for CYP2C19 activity.

High and variable frequencies of CYP2C19 mutations

Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3–6% of Europeans and Africans, and 13–23% of Asians. Greater than 99% of the poor metabolizer alleles in Asian populations are defined by two single base pair mutations (CYP2C19*2 and CYP2C19*3). We have recently reported an unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern Melanesia. To elucidate this further, a total of 5538 individuals from 24 populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had a poor metabolizer genotype (*2/*2, *2/*3 or *3/*3) with substantial variation among the populations (38–79%). The overall frequencies of CYP2C19*1 (wild-type), CYP2C19*2, and CYP2C19*3 were 0,223, 0.633, and 0.144, respectively. A significant linear correlation was observed between heterozygosity and South latitude (r = 0.552, P < 0.05). The genotype frequencies of 21 of the 24 populations were consistent with Hardy-Weinberg expectations (P > 0.05). Comparisons of genetic, linguistic and geographical patterns among populations suggest that short range gene flow is largely responsible for the current distribution of CYP2C19 alleles in Vanuatu. Taken together with previous studies of nuclear genetic loci of Pacific island populations, these data predict that the poor metabolizer genotype is common throughout Polynesia and Micronesia and may be even more prevalent in western Melanesia than in Vanuatu. This suggests that the majority of Pacific Islanders metabolize a wide variety of clinically important drugs to a significantly lower degree than the average European.

High and variable frequencies of CYP2C19 mutations

Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3-6% of Europeans and Africans, and 13-23% of Asians. Greater than 99% of the poor metabolizer alleles in Asian populations are defined by two single base pair mutations (CYP2C19*2 and CYP2C19*3). We have recently reported an unprecedentedly high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern Melanesia. To elucidate this further, a total of 5538 individuals from 24 populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had a poor metabolizer genotype (*2/*2, *2/*3 or *3/*3) with substantial variation among the populations (38-79%). The overall frequencies of CYP2C19*1 (wild-type), CYP2C19*2, and CYP2C19*3 were 0.223, 0.633, and 0.144, respectively. A significant linear correlation was observed between heterozygosity and South latitude (r = 0.552, P < 0.05). The genotype frequencies of 21 of the 24 populations were consistent with Hardy-Weinberg expectations (P > 0.05). Comparisons of genetic, linguistic and geographical patterns among populations suggest that short range gene flow is largely responsible for the current distribution of CYP2C19 alleles in Vanuatu. Taken together with previous studies of nuclear genetic loci of Pacific island populations, these data predict that the poor metabolizer genotype is common throughout Polynesia and Micronesia and may be even more prevalent in western Melanesia than in Vanuatu. This suggests that the majority of Pacific Islanders metabolize a wide variety of clinically important drugs to a significantly lower degree than the average European.

Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations

The increasing resistance of falciparum malaria to common antimalarial drugs has renewed interest in the compound proguanil normally metabolized to cycloguanil, a strong dihydrofolate reductase inhibitor, via the cytochrome P450 isozyme CYP2C19. The relationship between CYP2C19 genotypes and proguanil metabolism was therefore studied in 100 uncomplicated malaria patients on Malakula island in Vanuatu, where a CYP2C19-related poor metabolizer genotype status was known to be frequent. The patients (median age, 7 years) with Plasmodium falciparum or P. vivax infections, received proguanil treatment for 3 days in daily doses corresponding to adult doses of 300-500 mg. Capillary blood samples were collected on filter paper for determining both human CYP2C19 mutations by polymerase chain reaction and mutation-specific restriction enzyme digestion and blood concentrations of proguanil and its metabolites by high-performance liquid chromatography. The frequencies of the defective alleles, CYP2C19*2 and CYP2C19*3, were 0.57 and 0.25, respectively. The patients were genotyped as 68 CYP2C19-related poor metabolizers and 32 extensive metabolizers. Proguanil concentrations were higher and cycloguanil and 4-chlorophenylbiguanide concentrations were lower in poor compared to extensive metabolizers. Among the extensive metabolizers, 27 were heterozygous and five were homozygous for unmutated alleles. The tendency of an intermediate degree of proguanil metabolism in heterozygous extensive metabolizers as compared to homozygous extensive metabolizers and poor metabolizers suggests the trend towards the existence of a gene dose effect. Mild adverse events (mainly gastro-intestinal symptoms) were often reported and positively correlated with proguanil concentrations. The incidence was, however, similar in poor and extensive metabolizers. In conclusion, our data demonstrate an association between CYP2C19 mutations and poor metabolism of proguanil.

Clinical Pharmacology of Atovaquone and Proguanil Hydrochloride

Abstract Background: Atovaquone and proguanil hydrochloride is a new antimalarial combination that is used for treatment and prophylaxis of malaria. Methods: The clinical pharmacology of atovaquone and proguanil was reviewed. Results: Atovaquone is a highly lipophilic compound with low aqueous solubility, the absorption of which is limited by the rate and extent of dissolution. Dietary fat increases the rate and extent of atovaquone absorption, increasing AUC two- to threefold and C fivefold over fasting. Proguanil is rapidly and extensively absorbed regardless of food intake. Atovaquone is highly protein bound (&amp;gt; 99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely. Atovaquone is predominantly eliminated unchanged in feces, with negligible excretion in urine. Proguanil is partially metabolized and partially excreted unchanged in urine. Its principal metabolite, cycloguanil, is also excreted in urine. Metabolism of proguanil is mediated in the liver by the cytochrome P450 3A and 2C subfamilies.The elimination half-life of atovaquone is 2 to 3 days in adults and 1 to 2 days in children.The elimination half-lives of proguanil and cycloguanil are 12 to 15 hours in adults and children. Dosage adjustments based on body weight categories in children (Vi dose for 11-20 kg, h dose for &amp;gt;20-30 kg, 3/4 dose for &amp;gt;30-40 kg, and full dose for &amp;gt;40 kg) achieve plasma concentrations that are safe and effective during prophylaxis and treatment of malaria. No dose adjustments for race, proguanil metabolizer status, gender, or elderly patients are needed, or for patients with mild to moderately impaired renal or hepatic function. Conclusion: The clinical pharmacology of atovaquone and proguanil provides a rationale for the dosing regimens recommended for treatment and prophylaxis of malaria.

Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil.

Mutations in human CYP2C19 and parasite dihydrofolate reductase (dhfr) genes, related to poor metabolism of proguanil and resistance to cycloguanil, respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. To study this, 95 subjects with uncomplicated Plasmodium falciparum or Plasmodium vivax infections in Vanuatu received proguanil treatment for 3 days (adult relative dose of 300-500 mg/day) and were followed up for 28 days. A similarly high antimalarial efficacy against both infections was observed in 62 patients with CYP2C19-related poor metabolizer genotype and in 33 with extensive metabolizer genotype, even though blood cycloguanil was significantly more often detected in those with extensive metabolizer genotype than in those with poor metabolizer genotype. All 28 P. falciparum isolates had two dhfr mutations (residues 59 and 108), suggesting moderate resistance to cycloguanil. The results suggest that the parent compound proguanil has significant intrinsic efficacy against falciparum and vivax malaria independent of the metabolite cycloguanil.

Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian populations.

Genetic oxidation polymorphisms of debrisoquine (CYP2D6) and proguanil (CYP2C19) were studied in unrelated healthy South Pacific Polynesian volunteers recruited in the South Island of New Zealand. Phenotyping for CYP2D6 and CYP2C19 activities was determined using debrisoquine and proguanil, respectively, as probe drugs by measuring the urinary metabolic ratio of parent drug and its metabolite. Of 100 Polynesian subjects phenotyped, the metabolic ratio of debrisoquine ranged from 0.01 to 9.94. Therefore, all South Pacific Polynesians were classified as extensive metabolizers of debrisoquine according to previously established criteria of the antimode. The prevalence of poor metabolizers of debrisoquine (CYP2D6) in this Polynesian population is 0% (95% confidence interval of 0-3.6%). Oxidation polymorphism of CYP2C19 using proguanil as a probe was also studied in 59 Polynesian volunteers. The frequency distribution of the proguanil/cycloguanil ratio was bimodal. The proguanil/cycloguanil ratios for these subjects ranged from 0.09 to 34.4. Using a recommended proguanil/cycloguanil ratio cut-off point of 10 established in Caucasian populations, eight Polynesian subjects were identified as poor metabolizers of proguanil (CYP2C19), which corresponds to a poor metabolizer phenotype frequency of 13.6% (a 95% confidence interval of 5.9-24.6%). The incidence of poor metabolizer phenotypes for debrisoquine (CYP2D6) in South Pacific Polynesians appears to lower than in Caucasian populations, while the prevalence of poor metabolizers for proguanil (CYP2C19) in this ethnic population is higher. The frequencies of the poor metabolizer phenotype for debrisoquine and also for proguanil in South Pacific Polynesians are similar to those reported in Asian populations.

Hepatic cytochrome P450 CYP2C activity in psoriasis: studies using proguanil as a probe compound.

Retinol and proguanil are metabolised by the same family of hepatic cytochrome P450, i.e. CYP2C. We used proguanil as a probe to study CYP2C activity, and by implication retinol metabolism, in psoriasis. In vitro studies showed that retinol competitively inhibited the hepatic metabolism of proguanil to cycloguanil. Proguanil metabolism was assessed in 82 patients with chronic plaque psoriasis. Following proguanil orally (200 mg), urine was analysed for proguanil and cycloguanil. A proguanil to cycloguanil ratio < 1 signified extensive metabolism and a ratio > 10 poor metabolism. A wider range of ratios was observed in psoriasis than previously reported for normal subjects. The proguanil to cycloguanil ratio was assessed in 10 cases each of know severe and mild psoriasis. Low CYP2C activity was associated with severe psoriasis, poor metaboliser status occurring in 50% of the severe group, but in none of the mild cases, p < 0.01. These findings may indicate differences in retinoid metabolism in psoriasis.

The hydroxylation of omeprazole correlates with S-mephenytoin and proguanil metabolism.

This pharmacogenetic study was aimed at studying the pattern of oxidation of omeprazole in a Turkish population and testing whether omeprazole metabolism cosegregates with the genetically determined metabolism of mephenytoin and proguanil in Turkish subjects. The hydroxylation of omeprazole was measured in 116 unrelated healthy Turkish subjects after administration of a single oral dose of omeprazole (20 mg), using the ratio of omeprazole to 5-hydroxyomeprazole in plasma 3 h after dosing. To 31 subjects, who were phenotyped with omeprazole, mephenytoin (100 mg, p.o.) or proguanil (200 mg, p.o.) were administered at least 1 week apart. The S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil were determined from an 8-h urine collection. Based on the distribution of the log (omeprazole/hydroxyomeprazole) values and using the antimode value of 0.8, the frequency of poor metabolizers of omeprazole was estimated to be 7.7% (95% confidence interval 3-18%) which was similar to that in the other Caucasian populations (P = 0.54, Fisher's exact test). Three poor metabolizers of omeprazole were also classified as poor metabolizers of both mephenytoin and proguanil and no misclassification occurred with three phenotyping methods. All three methods separated poor or extensive metabolizer phenotypes with complete concordance. The ratio of omeprazole to hydroxyomeprazole correlated with the S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil. These results support the hypothesis that the oxidative metabolism of three different drugs may be catalyzed by the same cytochrome P450 enzyme.

High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu

High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu

Proguanil metabolism in relation to S‐mephenytoin oxidation in a Turkish population

The oxidation of proguanil was studied in 89 unrelated healthy Turkish volunteers after administration of proguanil (single dose, 200 mg, orally). Based on the distribution of the ratio of proguanil to cycloguanil excreted in urine, and using an antimode value of 15, the prevalence of poor metabolizers in a Turkish population was estimated to be 5.6% (95% confidence interval 2.0%-17.3%) which was similar to that in the other Caucasian populations. The relationship between the oxidative capacities of CYP2C19 for the two substrates, proguanil and mephenytoin, was studied in 39 subjects (two poor and 37 extensive metabolizers of proguanil). The two poor metabolizers of proguanil were also identified as poor metabolizers of S-mephenytoin and no misclassification by the two phenotyping methods was observed. The correlation between the metabolic ratio of proguanil to cycloguanil and the S/R-mephenytoin ratio as assessed by Spearman's rank test, was statistically significant (rs = 0.50, P < 0.001).

Japanese poor metabolizers of proguanil do not have an increased risk of malaria chemoprophylaxis breakthrough

Japanese poor metabolizers of proguanil do not have an increased risk of malaria chemoprophylaxis breakthrough

Evidence for the polymorphic oxidation of debrisoquine and proguanil in a New Zealand Maori population

The genetic oxidation polymorphisms of debrisoquine and proguanil were studied in a New Zealand Maori population. A bimodal distribution was observed in the 0-4 h urinary debrisoquine/4-hydroxydebrisoquine metabolic ratio. Of 101 Maori subjects phenotyped, five subjects (5%) were identified as poor metabolizers of debrisoquine, according to criteria established in studies of Caucasian populations. The prevalence of the debrisoquine poor metabolizer phenotype in the Maori appears to be similar to that reported for the Caucasian populations, but higher than that found in Asian (non-Caucasian) populations. The distribution of proguanil:cycloguanil (PG:CG) ratios obtained from 43 Maori subjects was highly skewed. Using a PG:CG ratio of 10 as the cut-off point, three Maori subjects (7%) were classified as poor metabolizers of proguanil. The incidence of the poor metabolizer phenotype of proguanil oxidation of 7% seems to be higher in Maori compared with Caucasian populations, but this is lower than the usual ranges (15-35%) reported in Asian populations.

The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides.

The effects of the CYP2C19 substrates, mephenytoin, methsuximide and mephobarbitone on the metabolism of proguanil and chlorproguanil by human liver microsomes were studied. All of the CYP2C19 substrates significantly inhibited (P < 0.05) the formation of both cycloguanil and chlorcycloguanil from their parent compounds. In the presence of mephenytoin (50 and 100 microM) the extent of proguanil cyclisation was decreased by 66% and 67% whilst the cyclisation of chlorproguanil was decreased by 51% and 70%, respectively. Methsuximide (50 and 100 microM) inhibited cycloguanil formation by 68% and 77% and chlorcycloguanil formation by 43% and 58%, respectively. In the presence of mephobarbitone (50 and 100 microM) the cyclisation of proguanil and chlorproguanil to their active metabolites was reduced by 24% and 42% and 48% and 63%, respectively. In addition, proguanil and chlorproguanil were shown to be mutual competitive inhibitors of metabolism to their triazine metabolites. In the presence of proguanil (50 and 100 microM) the Km value for chlorcycloguanil production was increased by 118% and 200%, respectively, with little change in Vmax. Similarly, chorproguanil (50 microM) increased the Km for the in vitro cyclisation of proguanil by 50% with no alteration in Vmax. These data suggest that both chlorproguanil and proguanil are metabolised in vitro by mephenytoin hydroxylase, CYP2C19.

Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

1. A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R-mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R-mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R-mephenytoin ratios < or = 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2. The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4-chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann-Whitney U-test). 3. There was no statistically significant correlation (Spearmans rs) between any index of proguanil metabolism and the sparteine metabolic ratio.