Working in bioanalytical chemistry.
The Biopharmaceutics Section, headed by Iain McGilveray, FCIC, is involved in a number of clinical projects based on bioanalytical chemistry; specifically development and application of methods for measurement of drugs and their metabolites in tissue, mainly in blood plasma. Typically, these projects are carried out in collaboration with local clinical units such as the Ottawa General Hospital, or Ottawa Heart Institute, although in some cases investigators from across Canada may be involved.
Cyclosporine (CYA) is an immunosuppressant drug which has dramatically decreased the tissue rejection rate in organ transplant patients. However, because of toxic effects, especially to kidney, the dose of the drug is critical and blood concentrations are carefully monitored. Unfortunately, interpretation of the results is complicated by non-specificity of the assays and the extensive metabolism of the cyclic undecapeptide. Seventeen CYA metabolites are known, all retain the cyclic peptide structure, with mono- and di-hydroxylation and/or N-demethylation biotransformations occurring. The immunosuppressive and toxic effects of these products remain largely unknown. BDR scientists, Jack Loo and Keith Gallicano have been involved in comparison of new immunoassay procedures, development of new specific HPLC methods and characterization of metabolites. It has been particularly interesting to find (in patients at Ottawa Civic Hospital, Dr. Jindal, nephrology) that CYA metabolite profiles of cardiac and renal transplant patients tend to differ. Gallicano has also been involved in monitoring plasma concentrations of the anti-AIDS drug Zidovudine (azidothymidine, AZT, scheme 1) again in comparing immunoassay and HPLC procedures to improve dosing instructions in patients with impaired kidney or liver function.
The ratio of unchanged drug to glucuronide metabolite may be particularly important in these patients.
The calcium channel antagonist Nifedipine and its metabolites (scheme 2) have been challenging for Saeed Qureshi and Bob Brien to analyze in plasma to support a number of clinical investigations coordinated by Sylvie Laganiere. The IV dosing schedule to examine the potential for Nifedipine to control acute hypertensive episodes, occurring after the coronary artery bypass grafting, was evaluated.
Nifedipine is unstable to light and one of the photodegradation products is also a metabolite. The modified analytical procedure uses gas-liquid chromatography with electron capture detection of the nitro function to separate unchanged drug from metabolites to attain sensitivities of 0.5 ng/mL. Overall, the drug seems to be effective at higher doses, but other more potent related dihydropyridines such as Nitrendipine may be more effective and may be investigated in the future.
A major problem for drug regulatory agencies is that most drugs are foreign organic substances metabolised prior to excretion. As well as age-related changes in metabolic processes, there are segments of the population who may unknowingly be genetically poor metabolisers for particular drug metabolism pathways, with the result that drug dosage should be reduced to avoid adverse effects. For example N-acetylation, which occurs with a number of drugs, such as the antitubercular isoniazid and the cardiovascular agents hydralazine and procainamide, shows a bimodal distribution 40:60 between extensive and poor metabolisers in caucasians, while more than 90% + of Japanese and Canadian Inuit are extensive metabolisers. Fewer adverse effects with these drugs are reported in the latter group.
Poor oxidation of aromatic as well as side-chain functions is less well-established as a genetically affected pathway. This has been examined by use of an antihypertensive, Debrisoquine, (scheme 3) as a phenotype marker.
However, this drug itself is not benign and, along with other laboratories in Canada, the branch has begun to look at Methoxyphenamine as a marker. Methoxyphenamine, although withdrawn in Canada for lack of sales, was marketed as a non-prescription drug cough & cold remedy, and the single dose used in phenotyping is considered safe. There only appear to be about 10% of the Caucasion population who are poor Debrisoquine or Methoxyphenamine metabolisers. It is the ratio of the excretion of drug, O-demethyl and N-demethyl metabolites in urine (scheme 4) for eight hours after dosing which allows categorization of metabolisers.
Drugs which could be affected by poor metabolism include metoprolol, a 13-blocker, and recently Encainide, scheme 5, a potent drug which suppresses irregular heart beats and which has been examined in patients by Laganiere in collaboration with the Ottawa Heart Institute and other North American centres. It is considered possible that poor metabolisers could accumulate more drug, although the O-desmethyl metabolite, which would be present in normal (or extensive) metabolisers, is also active and the effects may not differ in the two groups.
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|Title Annotation:||Canada's Bureau of Drug Research|
|Author:||McGilveray, Iain J.|
|Publication:||Canadian Chemical News|
|Date:||Nov 1, 1989|
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