Einosuke Tanaka

Gender-related differences in pharmacokinetics and their clinical significance

In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex‐specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side‐effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side‐effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

Clinically important pharmacokinetic drug–drug interactions: role of cytochrome P450 enzymes

Drug–drug interactions have become an important issue in health care. It is now realized that many drug–drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra‐hepatic tissues and many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple‐drug therapies. In the future, it may help to identify individuals at greatest risk of drug interactions and adverse events.

Clinically significant pharmacokinetic drug interactions between antiepileptic drugs.

Pharmacokinetic interactions between antiepileptics represent a major potential complication of epilepsy treatment because drug combinations are common. This review discusses pharmacokinetic drug interactions of clinical significance involving antiepileptics and cytochrome P450 (CYP). Most commonly used antiepileptics are eliminated through hepatic metabolism, catalysed by the enzymes CYP2C9, CYP2C19 and CYP3A4 and uridine diphosphate glucuronosyltransferase (UDGPT). Antiepileptics are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition. Phenytoin, phenobarbiral, primidone and carbamazepine induce CYP and UDPGT enzymes while valproic acid inhibits them.

Clinically significant pharmacokinetic drug interactions with psychoactive drugs : antidepressants and antipsychotics and the cytochrome P450 system

Psychotherapeutic drugs (antipsychotics and antidepressants) are widely used for treating anxiety. Many psychotherapeutic drugs are metabolized mainly by cytochrome P450 (CYP)2C19 and CYP2D6, and are often administered with other drugs. Therefore, it is necessary to be careful when coadministering psychotherapeutic drugs whose metabolism might be inhibited by other drugs. In particular, selective serotonin reuptake inhibitors (SSRIs) inhibit the metabolism of psychotherapeutic drugs mediated by CYP2C19 and CYP2D6. It is useful to phenotype CYP2C19 and CYP2D6 (extensive metabolizers or poor metabolizers) before giving such medication.

How useful is the ‘cocktail approach’ for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo?

Relatively selective in vivo substrate probes have been developed for several major CYP isoforms involved in oxidative drug metabolism. There are basically two in vivo methods for identifying the phenotype. One method, the selective (CYP‐specific) phenotyping method, involves administering one single probe drug, whereas the other is a mixed phenotyping or ‘cocktail’ method involving the simultaneous administration of multiple probe drugs, specific for the individual P450. At present, caffeine and chlorzoxazone are used most often as probe drugs for CYP1A2 and CYP2E1, respectively, but these are not necessarily the best probe drugs. Of the potential probe drugs for CYP2C9, CYP2C19, CYP2D6 and CYP3A4, none is really useful. Despite current limitations, the cocktail method for obtaining information about multiple CYP activities in a single experimental session is likely to be more widely used as a screening or phenotyping method for humans in the future.

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.

Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics.

Toxicological Interactions Between Alcohol and Benzodiazepines

Background: We review recent findings on the toxicological interactions between alcohol (ethanol) and benzodiazepines, and the combined use of benzodiazepines and alcohol in fatal poisoning. Acute ingestion of alcohol combined with benzodiazepines is responsible for several toxicological interactions that can have significant clinical implications. In general, metabolism of these drugs is delayed when combined with acute alcohol ingestion although some reports suggest otherwise. Alternately, the drugs metabolized during chronic alcohol ingestion have an increased clearance. The net effect may also be influenced by internal (e.g., disease, age) and external (e.g., environment, diet) factors. Fatal poisoning involving coadministration of alcohol and benzodiazepine, especially triazolam, continues to be a serious problem.

Forensic analysis of eleven cyclic antidepressants in human biological samples using a new reversed-phase chromatographic column of 2 μm porous microspherical silica gel

A high-performance liquid chromatographic method has been developed for the forensic analysis of eleven frequently used cyclic antidepressant drugs (ADSs) (amitriptyline, amoxapine, clomipramine, desipramine, dosulepine, doxepin, imipramine, maprotiline, melitracen, mianserine and nortriptyline) using a recently developed reversed-phase column with 2 microm particles for the analysis of biological samples. The separation was carried out using two different C8 reversed-phase columns (column 1: 100 mm X 4.6 mm I.D., particle size 2 microm, TSK gel Super-Octyl; column 2: 100 mm X 4.6 mm I.D., particle size 5 microm, Hypersil MOS-C8) for comparison. The mobile phase was composed of methanol-20 mM KH2PO4 (pH 7) (60:40, v/v) and the flow-rate was 0.6 ml/min for both columns. The absorbance of the eluent was monitored at 254 nm. When the eleven drugs were determined, the sensitivity with the 2 microm particles was about five times greater than with the 5 microm particles. Retention times on column 1 were shorter than those on column 2. These results show that the new ODS column packing with a particle size of 2 microm gives higher sensitivity and a shorter analysis time than the conventional ODS column packing when applied to the analysis of biological samples.

Update: genetic polymorphism of drug metabolizing enzymes in humans

The cytochrome P450 (P450 or CYP) monooxygenases, CYP2D6, CYP2C19, CYP2E1 and CYP2C9, and non‐P450 monooxygenases, N‐acetyltransferase, thioprine methyltransferases and dihydropyrimidine dehydrogenase, all display polymorphism. CYP2D6 and CYP2C19 have been studied extensively and, despite their low abundance in the liver, they have been found to catalyse the metabolism of many drugs. CYP2D6 has many allelic variants, whereas CYP2C19 has only two. Most variants are translated into inactive, truncated proteins or fail to express protein. There is, as yet, no clear information about CYP2E1 polymorphism. In addition, genetic differences in certain foreign‐compound metabolizing enzymes, such as Phase II enzymes, have been shown to be associated with an increased risk of developing environmentally and occupationally related diseases such as cancer.

In vivo function tests of hepatic drug‐oxidizing capacity in patients with liver disease

Aminopyrine, antipyrine and trimethadione have been widely used for some time as probe drugs to assess non‐selective P450 liver function. They have proved useful in evaluating pre‐ and post‐operative liver function when performing surgery, transplantations, etc., in addition to a general evaluation of liver function and drug interactions. Progress has recently been made both in these non‐selective P450 function tests and in the analysis of drug‐metabolizing enzymes at a molecular level, which has resulted in more selective P450 function tests.