Drugs labeled with stable isotopes have been successfully used in pharmacokinetic drug interaction studies. This technique provides precise information on the mechanisms responsible for drug interactions, e.g., changes in clearance due to induction or inhibition of drug metabolism, bioavailability, and volume of distribution. It offers the advantage that detailed studies on the pharmacokinetics and metabolism of a drug can be conducted in a clinical setting during steady-state conditions, thus avoiding problems in patient management that can arise from studies in which drug is withdrawn.

Carbamazepine↗

PubMedDate not supplied

Influence of pharmacogenetics on drug disposition and response.

1. Pharmacogenetics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. 2. Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common inherited enzymopathy affecting approximately 400 million people. The main clinical complication associated with G6PD deficiency is haemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans. 3. The activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g. N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. The gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. The other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

Cytochrome P-450 Enzyme System↗

PubMedDate not supplied

Defective oxidation of drugs: pharmacokinetic and therapeutic implications.

Explore the source record for details and available documents.

Amobarbital↗

PubMedDate not supplied

Application of stable labelled drugs in clinical pharmacokinetic investigations.

Explore the source record for details and available documents.

Biological Availability↗

PubMedDate not supplied

Carbamazepine metabolism in man. Induction and pharmacogenetic aspects.

The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of 15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1. As it has been suggested that 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway. Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine. The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.

Adult↗

PubMedDate not supplied

Clinical pharmacokinetics of verapamil, nifedipine and diltiazem.

The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Availability↗

PubMedDate not supplied

Identification of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and (3-carboxymethylthio)lactic acid as major human biotransformation products of S-carboxymethyl-L-cysteine.

S-Carboxymethyl-L-cysteine (CMC) is used both as an orally administered mucolytic agent and as a probe drug for uncovering polymorphic sulfoxidation of other sulfur-containing drugs in humans. However, several recent studies could not confirm the formation of significant amounts of urinary sulfoxides of CMC or its decarboxylation product S-methyl-L-cysteine. The metabolism of CMC and a 13C-labeled isotopomer was therefore reinvestigated in 11 and 14 humans, respectively, and emphasis was laid on monitoring of potential alternative metabolic pathways. Combined capillary gas chromatography/electron impact or negative-ion chemical ionization mass spectrometry employing stable isotope-labeled analogues as internal standards were used for identification and quantification of CMC metabolites in human urine. Three nitrogen-free metabolites that were identified as thiodiglycolic acid (TDGA, mean: 19.8% of the dose/24 hr), thiodiglycolic acid sulfoxide (TDGA-SO, mean: 13.3% of the dose/24 hr), and (3-carboxymethylthio)lactic acid (TLA, mean: 2.1% of the dose/8 hr), cumulatively account for about one-third of the dose during a urinary collection period of 24 hr. In addition, trace amounts of both TDGA and TLA exist as endogenous components in urine from persons not administered exogenous CMC at levels of about 5 and 1 nmol/ml, respectively. Both major metabolites TDGA and TDGA-SO, that were not considered in previous sulfoxidation phenotyping, are predominantly excreted after 8 hr. These results demonstrate the existence of a pyruvate-like metabolic pathway and suggest the necessity of a revision of the hitherto accepted biotransformation route of CMC in humans.

Biotransformation↗

PubMedDate not supplied

A nuclear magnetic resonance study of sparteine delta metabolite structure.

Originally, the enamines 2,3- and 5,6-didehydrosparteine (2a and 3a, respectively) had been characterized by GC/MS as metabolites after administration of (-)-sparteine sulfate (1a.H2SO4). Since the existence of free enamines in aqueous medium seemed rather doubtful, the metabolism of (-)-sparteine was reinvestigated by high-resolution 1H-, 2H-, and 13C-NMR spectroscopy. When synthetic 1,2-didehydrosparteinium monoperchlorate (4a.ClO4) is dissolved in aqueous medium at pH 4-9, sterically uniform (2S)-hydroxysparteine (6a) is formed, as is proven unequivocally by 1H- and 13C-NMR. However, at pH less than or equal to 2, this carbinolamine eliminates water under reconstitution of the iminium structure 4a. No carbinolamine is formed, in contrast, from synthetic 1,6-didehydrosparteinium monoperchlorate (5a.ClO4). Upon oral application of [2R-2H]sparteine (1b), as the sulfate, the respective carbinolamine and iminium structures 6b and 5b are identified in the urines by 2H-NMR spectroscopy. Reversed-phase TLC likewise confirms the different structural principle of the two main sparteine metabolites. The free enamine bases, characterized by GC/MS, thus must be regarded as artifacts, formed in the work-up requisite for GC analysis.

Chromatography, Thin Layer↗