Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.

OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.

Lack of effect of chloroquine on the debrisoquine (CYP2D6 and S-mephenytoin (CYP2C19) hydroxylation phenotypes.

The effects of chloroquine (CHQ) on debrisoquine hydroxylase (CYP2D6) and S-mephenytoin hydroxylase (CYP2C19) were assessed in 11 black Zimbabwean and 12 white Swedish healthy volunteers. The activity of CYP2D6 was measured as the urinary debrisoquine to 4-hydroxydebrisoquine metabolic ratio and that of CYP2C19 as the urinary S- to R-mephenytoin enantiomer ratio (S/R). There were no statistically significant differences in either metabolic ratio as a result of prophylactic or loading doses of CHQ. This indicates that CHQ does not inhibit CYP2D6 or CYP2C19 in vivo and is unlikely to compromise the metabolism of substrates for these two enzymes. It is, therefore, also unlikely that residual CHQ in populations under study will interfere with phenotyping of either CYP2D6 or CYP2C19.

Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry.

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of 14C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22 +/- 2% (mean +/- S.D.) and 25 +/- 4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21 +/- 5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76 +/- 15% (mean +/- S.D.) of the total excreted radioactivity on day 1 and 97 +/- 1% on day 6. HPLC--tandem mass spectometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.

Pharmacokinetics of metrifonate and its rearrangement product dichlorvos in whole blood.

Six male healthy volunteers were given single oral doses of 7.5 mg/kg of metrifonate and concentrations of metrifonate and dichlorvos were determined in whole blood using a standardized sampling procedure. Blood was collected in test tubes containing equal volumes of 0.74 M phosphoric acid for the determinations of metrifonate and dichlorvos with gas chromatography and mass spectrometry at different time points for up to 24 hr. Cholinesterases were also determined in blood haemolyzed with water. Metrifonate was quickly absorbed with a Cmax of 50.5 +/- 18.9 mumol/l which was obtained between 0.17 to 1 hr after drug intake. Mean whole blood t1/2, Clo and AUC were 2.07 +/- 0.24 hr, 0.34 +/- 0.06 l/hr/kg and 89.2 +/- 16 mumol.hr/l respectively. The concentrations of dichlorvos closely followed those of metrifonate with a constant ratio of 0.01 to 0.02. The concentrations of metrifonate were detectable for up to 8 hr but those of dichlorvos had fallen below the level of determination by this time. Both plasma and red blood cell cholinesterases were readily inhibited and were still low after 24 hr. None of the volunteers complained of side effects.

Determination of metrifonate and dichlorvos in whole blood using gas chromatography and gas chromatography-mass spectrometry.

Analytical methods for determining metrifonate and dichlorvos in whole blood and a sampling procedure suitable for pharmacokinetic studies in man are described. Metrifonate concentrations were determined after chloroform extraction using gas chromatography-nitrogen-phosphorus detection. The within-assay coefficients of variation were 4 and 9% at 19.4 and 0.8 mumol/l (limits of determination), respectively. Dichlorvos was determined using gas chromatography-mass spectrometry of toluene extracts. The within-assay coefficients of variation were 2 and 5% at 225 and 50 nmol/l (limits of determination), respectively. Since both substances are chemically unstable, the blood was collected by dripping it directly from the vein into 0.74 M phosphoric acid.