Metabolic drug interactions in man : methodological aspects on in vivo studies

Abstract

The aim of this thesis was to investigate methodological aspects on in vivo metabolic drug interaction studies in man. Five pharmacokinetic studies in healthy persons or patients are presented. Together, they represent a set of model studies to evaluate the occurrence of, and extent of metabolic drug interactions in vivo. They are all based on previous in vitro findings, and were designed to take advantage of the current knowledge concerning specificity and selectivity of drug metabolising enzymes and interindividual differences in drug metabolising capacity. A special focus was the study of omeprazole as a probe for, and ketoconazole as an inhibitor of the CYP3A4 enzyme.

Ketoconazole (repeated doses) markedly inhibited the CYP3A4 mediated sulphoxidation of omeprazole (single doses) in a dose-dependant manner, in both extensive and poor hydroxylators (CYP2C19) of omeprazole. This study confirms that omeprazole sulphoxidation is the main metabolic pathway in individuals devoid of CYP2C19 activity, and shows that these subjects develop very high omeprazole concentrations during ketoconazole co-administration. Tolterodine, which is mainly metabolised by CYP2D6, was given in repeated doses to both poor and extensive metabolisers (CYP2D6), but did not influence the metabolism (as indicated by metabolite ratios) of single doses of the probe drugs debrisoquine (CYP2D6), omeprazole (CYP2C19 and CYP3A4) or caffeine (CYP1A2), given on three consecutive days. Tolterodine is thus unlikely to inhibit the metabolism of drugs eliminated via these enzymes. Data from the above studies, together with data from two other omeprazole studies, support the use of omeprazole as a probe for the evaluation of CYP3A4 activity, as well as its previously suggested use as a probe for CYP2C19. Fluvoxamine (a CYP1A2 inhibitor), but not ketoconazole, had a significant effect on the clearance of intravenously administered ropivacaine. This study confirms in vitro and in vivo pharmacokinetic findings indicating CYP1A2 as the most important enzyme in ropivacaine metabolism, and shows that CYP1A2 inhibitors may cause clinically relevant interactions with ropivacaine. Concomitant administration of single doses of sirolimus and diltiazem lead to increased sirolimus exposure in 16 out of 18 subjects, presumably by inhibition of intestinal CYP3A4 and/or P-glycoprotein. This interaction needs further evaluation during steady-state conditions, but does point to the possibility of other CYP3A4 inhibitors interacting with sirolimus. Lamotrigine drug interactions were studied in a therapeutic drug monitoring material including 104 patients. A widespread intra- and interindividual variation in the concentration/dose ratio for lamotrigine could largely be explained by pharmacokinetic interactions with phenytoin, carbamazepine, phenobarbital (all three inducing lamotrigine metabolism) and valproic acid (an inhibitor of lamotrigine glucuronidation).

The systematic knowledge concerning drug metabolising pathways and mechanisms of metabolic drug interactions is growing. Effective and informative in vitro studies are already in use, and are also being continuously developed. So far, there is no universally reliable method to extrapolate in vitro findings to in vivo clinical conditions. However, with the current knowledge of drug metabolism and a base of in vitro study methods, it is possible to use a confined number of well designed interaction studies in vivo, with specific and selective inhibitors and probe drugs in appropriate doses, given to panels of extensive and poor metabolisers. Such studies, in combination with routine evaluation of data from therapeutic drug monitoring, as exemplified in this work, can provide clinically useful information concerning pharmacokinetic drug interactions, leading to safer, better individualised and more cost-effective drug treatment.