Search

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.

1. The major metabolite of the antischistosomal compounds desoxymansil (I) and oxamniquine (II) in various species is the 6-carboxylic acid (III). Mouse, rabbit, dog and monkey, but not rat, yield a second carboxylic acid metabolite (V) formed by oxidation of the isopropylaminomethyl side-chain.2. Desoxymansil (I) incubated with microsomal preparations of rat, mouse or rabbit liver was metabolized to oxamniquine (II) by hydroxylation of the 6-methyl substituent; N-dealkylation of the isopropyl group did not occur. Oxamniquine (II) incubated with liver microsomal preparations did not undergo N-dealkylation, but the amine analogue (IV) of desoxymansil was deaminated by the liver microsomal preparations.3. Oral administration of the amine analogue (IV) of desoxymansil to rat led to the excretion of the acid (V) in the urine, indicating that the rat can deaminate IV. Deamination of IV was shown to be catalysed by the mitochondrial fraction of liver, and mouse and rat showed similar levels of enzyme activity.4...

The uptake and retention of drug-related material by Schistosoma mansoni was studied in the mouse host following a single oral or intramuscular does (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 matebolites of oxamniquine win vitro.

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.

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.

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.

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.

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

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 < 0.01) and Swedes (rs = −0.84; P < 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. Clinical Pharmacology and Therapeutics (1984) 36, 374–378; doi:10.1038/clpt.1984.190

1. The metabolism of a new schistosomicide, 2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline, was investigated in the mouse, rat, rabbit and rhesus monkey.2. All the species studied converted the compound to its 6-hydroxymethyl analogue, which showed greater schistosomicidal activity in vivo than the parent drug.3. Several other metabolites were also produced by oxidation at the 2- and/or 6-positions to give carboxylic acid derivatives. None of these metabolites showed biological activity.4. A species difference was apparent, since the 2-carboxylic acid metabolite was not detected in the urine or bile of the rat.

1. 5,7-Dinitroindazole was extensively metabolized in both rats and mice. The principal biotransformations were nitro group reduction and aromatic hydroxylation.2. Selective reduction of the 7-nitro group to yield the 7-amino derivative occurred in both species in vivo. The same specificity of reduction was evident when dinitroindazole was incubated with a mixed culture of rat faecal microorganisms.3. A species difference in conjugation was found. In the mouse the major urinary excretion product was the N-glucuronide of the 7-amino derivative but this was not found in rat urine, acetylation of the 7-amino group being the preferred biosynthetic reaction.4. This 7-acetamido derivative is the probable precursor of two other metabolites in the rat. One of these has been identified as 3-hydroxy-5-nitro-7-acetamidoindazole and the other may be an N-hydroxylated derivative.