Polymorphic N-acetyltransferase (NAT2) genotyping of Emiratis.

Polymorphic N-acetyltransferase (NAT2) genotypes were determined in 106 unrelated Emiratis by PCR-RFLP analysis to obtain estimates of allele frequencies. Thirteen different genotypes were found, four associated with the rapid acetylator phenotype and nine with the slow acetylator phenotype. Among 67 phenotypically slow acetylators, there was 100% concordance between phenotype and genotype. Among 39 phenotypically rapid acetylators, 37 possessed at least one wild type allele; a 95% concordance with genotype. Seven different NAT2 alleles associated with slow acetylation were found. The commonest was a NAT2*5 type (C481T) allele which occurred with a frequency of 0.53, a significantly higher frequency than has been reported for other ethnic groups. A second slow allele, a NAT2*6 type (G590A), occurred with a frequency of 0.21. The most common genotypes found were NAT2*5/*5 homozygotes, NAT2*5/*6 heterozygotes and NAT2*4/*5 heterozygotes with frequencies of 0.25, 0.25 and 0.22 respectively. The high overall prevalence of alleles associated with slow acetylation (173/212; 81.6%) among Emiratis is consistent with previously reported high frequency of the slow acetylator phenotype in Arabs. Two apparently new slow alleles were identified but have not yet been fully characterized. One appears to be a NAT2*5 variant allele. The other uncharacterized allele appears likely to contain an entirely new mutation associated with slow acetylation.

Inter-subject and ethnic differences in paracetamol metabolism.

The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.

The effect of chloroquine on paracetamol disposition and kinetics.

The effect of chloroquine on paracetamol kinetics and disposition was investigated in six healthy male Ghanaian volunteers. Chloroquine administration shortened the time taken to reach peak plasma paracetamol concentration (tmax) in five of the volunteers. Peak plasma paracetamol concentration (Cmax) was significantly increased by chloroquine administration. The area under the plasma paracetamol concentration-time curve was also significantly increased by chloroquine administration. There was, however, no effect of chloroquine on paracetamol metabolism.

Whole-blood single-dose kinetics of chloroquine and desethylchloroquine in Africans.

The whole-blood kinetics of chloroquine and desethylchloroquine were studied in five healthy Ghanaian subjects. Chloroquine was rapidly absorbed, and peak concentrations were reached within 2 h. The drug disappeared from blood in a multiexponential manner, and the mean terminal half-life from day 7 to day 28 was 13 days. Desethylchloroquine concentrations were generally higher than those of chloroquine after 48 h. Renal clearance accounted for 65% of the apparent total clearance of chloroquine. The estimated mean total urinary recovery of the drug and its desethyl metabolite was 80% of the dose. Whole-blood concentrations of chloroquine offer some advantages compared with plasma concentrations, as this drug concentrates in the formed elements, and special precautions must be taken to obtain representative plasma concentrations.

Dissociation of co-regulatory control of debrisoquin/phenformin and sparteine oxidation in Ghanaians.

The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.

Inter-ethnic difference in sparteine oxidation among Ghanaians and Germans.

Sparteine oxidation, which exhibits genetic polymorphism in various Caucasian populations, was studied in 154 unrelated Ghanaian subjects. Mean total urinary recovery of sparteine and 2- and 5-dehydrosparteines (56.6 +/- 16.6% of the dose) was not different from Caucasians. In contrast to Caucasians, amongst whom 6.3 to 9% of the population are poor metabolizers (PM), no PM subject was observed in the Ghanaian population sample. The data appear to indicate allelic differences between Caucasians and Ghanaians in the gene encoding the synthesis of the P-450 isozyme involved in polymorphic sparteine oxidation.

Nortriptyline and debrisoquine hydroxylations in Ghanaian and Swedish subjects.

Eleven Ghanaian and 12 Swedish subjects phenotyped with a debrisoquine (D) hydroxylation test were given a single oral dose of nortriptyline (NT). Much the same percentage of the given NT dose was excreted as 10-hydroxy-NT (10-OH-NT) by Ghanaians (43.1%) and Swedes (49.2%). There was a close correlation between plasma clearance of NT by 10-hydroxylation and the D metabolic ratio (D/4-OH-D in urine) in the Ghanaians (rs = -0.95; P less than 0.01) and Swedes (rs = -0.84; P less than 0.01). The E-isomer of 10-OH-NT is the major isomer in both Ghanaians (76% to 92% of total 10-OH-NT) and Swedes (78% to 95%). It is suggested that the E-10-hydroxylation of NT and the 4-hydroxylation of D are similarly coregulated in Ghanaians and Swedes.

Influence of double genetic polymorphism on response to sulfamethazine.

Combined effects of a double genetic polymorphism on sulfamethazine-induced changes in erythrocyte-reduced glutathione (GSH) concentration were investigated in 16 healthy Ghanaian men. The subjects were divided into four subgroups on the basis of their glucose-6-phosphate dehydrogenase (G-6-PD) activity levels and acetylator phenotypes. Each received a single oral dose of sulfamethazine (1.5 gm). Erythrocyte concentration of GSH and plasma concentrations of drug were determined in samples taken at specific times after dosing. Sulfamethazine treatment induced a decrease in erythrocyte GSH concentration in all subjects. The degree of exposure to sulfamethazine was greater in slow acetylators, as evidenced by higher plasma concentrations, longer half-lifes, and greater area under the plasma concentration-time curves. The greatest decrease in GSH concentration occurred in subjects who where both G-6-PD deficient and phenotypically slow acetylators. In these subjects the effect of the double genetic defect was approximately additive. Drug-induced hemolysis is associated with a low erythrocyte GSH concentration. Our data suggest that slow acetylator status is likely to increase susceptibility to hemolysis in G-6-PD-deficient individuals exposed to potentially hemolytic arylamines.

Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians.

The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4-hydroxylation of debrisoquin in Ghanaians was polymorphic. Three phenotypes were observed: homozygous extensive metabolizers (58%), heterozygous extensive metabolizers (36%), and homozygous poor metabolizers (6%). In contrast, British Caucasians are primarily monomorphic extensive metabolizers (92%) and homozygous poor metabolizers comprise 8% of the population. Urinary recovery of the drug and its hydroxylated metabolites was significantly less in the Ghanaian subjects. In both Ghanaian and British populations, aromatic hydroxylation producing 5-, 6-, 7-, and 8-hydroxydebrisoquin was shown to parallel the alicyclic 4-hydroxylation of debrisoquin, and thus to be controlled by the same gene locus. Debrisoquin is advocated as a tool for uncovering polymorphism in drug oxidation and its interethnic variations.

Uptake of [14C]oxamniquine by Schistosoma mansoni.

The uptake and retention of drug-related material by Schistosoma mansoni was studied in the mouse host following a single oral or intramuscular dose (50 mg/kg) of [14C]oxamniquine. Male worms took up more labelled material than did female worms but the amount in each particular sex of worm was found to be similar after both routes of administration. Exposure of worms was therefore independent of the route of administration. Six days after drug administration, at the time of an hepatic shift, significantly more drug-related material was present in male worms than in female worms. Examination of worms recovered from mice 4 h after treatment showed that metabolites of oxamniquine constituted 70--90% of the drug-related material present in the worms. Both sexes of worms were able to take up metabolites of oxamniquine in vitro.

Determination of oxamniquine in serum.

A method for the analysis of oxamniquine in serum (or plasma), sensitive to 10 ng/ml, was developed. Oxamniquine and a close structural analog as the internal standard were extracted from serum with ether. After derivatization with N,O-bis(trimethylsilyl)acetamide, oxamniquine was determined as its trimethylsilyl ether derivative by GLC using an electron-capture detector. The method was developed to study serum concentration profiles of different dosage forms of oxamniquine.

The metabolism of oxamniquine - a new schistosomicide.

The metabolism of oxamniquine, 6-hydroxymethyl-7-nitro-2-isopropylaminomethyl-1,2,3,4-tetrahydroquinoline, has been studied in the mouse, rat, hamster, rabbit, rhesus monkey, dog and man. Urinary excretion is a major route of elimination in man. The compound is converted to two metabolites, the major one arising from oxidation of the 6-hydroxymethyl group to a carboxyl group and the other by oxidation of the side chain to give the 2-carboxylic acid. There is a species at the dose levels used since both acidic metabolites were found in appreciable quantities only in the urine of mouse, rabbit, hamster and dog. The 2-carboxylic acid was not found in the urine of rhesus monkey and rat and occurred in only trace amounts in human urine.

Cardiovascular effects of a new inotropic drug in dog and normal man.

Cardiovascular effects of 1-butyl-3(1-(6,7-dimethoxyquinazolin-4-yl) piperidin 4 yl urea) (BDPU) were studied in 16 anesthetized dogs and in 7 healthy male volunteers. In animal experiments intravenous doses of 100, 250, and 500 mug/kg/min produced dose-related, significant increases in cardiac output and peak left ventricular dp/dt. No changes in heart rate and blood pressure occurred at 100 mug/kg/min, whereas higher doses caused falls in both systolic and diastolic blood pressures, accompanied by significant rises in heart rate. Inotropic effects could also be demonstrated in man. Changes of the systolic time intervals were dose-related and began at 64 mug/kg/min. At 250 mug/kg/min, the highest dose administered, the pre-ejection period decreased by 14.8 +/- 4.42 msec and its ratio with left ventricular ejection time by 0.049 +/- 0.017 against their respective control values (p less than 0.01). In contrast to animal experiments, no hypotension or tachycardia was observed in any subject. Pharmacokinetic studies showed a plasma elimination half-life of 76 +/- 3 min (mean +/- SE). There were no subjective side effects and standard laboratory tests were not altered, but there was a slight but significant rise in the urinary enzymes, lactic dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT), which persisted up to 7 days.