Olanzapine and CYP1A2 genotypes

Shirley et al, Neuropsychopharmacology (2003) 28, 961–966

Olanzapine, an atypical antipsychotic agent used in the treatment of schizophrenia, is metabolized to 10- and 4'-N-glucuronide, 4'-N-desmethylolanzapine via CYP1A2. Here is report demonstrating the relationship between (orally administered) olanzapine clearance/F and the metabolic ratio (PMR = 17X/137X) measured using caffeine.

Laika et al, The Pharmacogenomics Journal (2010) 10, 20–29

Notwithstanding the lack of predictive value of CYP1A2 genetics on CYP1A2 activity, here is a study looking at the effect of the presence of CYP1A2*1F allele on olanzapine steady state plasma concentrations, in the presence/absence of inducers such as smoking and carbamazepine.

While both inducers and *1F/*1F genotype showed significant effects on average olanzapine concentrations, the scatter within each group remains very large, and is clearly not explained by either effects.

CYP1A2

The CYP1A gene family is a very old one, and the enzyme is found in all vertebrates. In humans there are 2 paralogous members of the family; CYP1A1 expressed predominantly in the lung, and CYP1A2 expressed in the liver.

The CYP1A enzymes very likely evolved to deal primarily with environmental polycyclic hydrocarbons. The activity of CYP1A2 varies considerably and may be easily phenotyped using caffeine as a probe substrate to generate a metabolic ratio.

The metabolic ratio in the population displays a broad unimodality which disguises the fact that the gene is highly polymorphic. The activity of the enzyme is not easily predicted by the genotype as the enzyme is very easily induced by exposure to environmental hydrocarbons. The gene haplotypes may in fact be associated with low or high inducibility of the enzyme.

Inhaled hydrocarbons through cigarette smoking is a common inducer of CYP1A2. In Singapore we are also seasonally exposed to high levels of environmental hydrocarbons as a result of forest fires in the region. The maximum exposure tends to be during dry periods, and when the prevailing winds blow in from the West. These tend to be during the July-November period. It is currently unclear to what extent this has affected our population average CYP1A2 activity.

The most comprehensive examination of CYP1A2 in Chinese is that reported by Chen et al 2005. They were able to demonstrate that haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects. These haplotype pairs account for approximately 6% and 25% of the population respectively.

The Cytochrome p450 enzymes belong to probably the largest gene superfamilies known. Comprising more than 6500 genes, there are 57 enzymes alone in humans, involved with the metabolism of endogenous and exogenous compounds. The original CYP450 gene is a very ancient one, tracing its origins back perhaps 2 billion years. All the known members of the gene superfamily probably arose from this ancient precursor through gene duplications etc.

This vast numbers of members is required at least in part for the metabolism of endogenous substrates, but it is likely that many have developed for the purpose of dealing with environmental toxicants which enter the body through mucosal barriers of the gut, and lungs, but also the skin. As the main route for the entry of environmental chemicals is via oral ingestion, the largest amount of p450 is found in the liver, as well as the intestinal linings.

The largest amount present in the liver belong to the 3A family. However, the abundance of the enzymes does not translate directly to the relatively importance of the enzyme with respect to the metabolism of pharmaceuticals. This is likely because the enzymic isoforms have evolved primarily for environmental chemicals, while pharmaceuticals as a subset of environmental chemicals, are chemicals with a very short and recent history.

The 3 most important families for pharmaceutical detoxification are CYP3A, CYP2D6 and CYP2C.

The recognition of CYP450's role in dealing with environmental chemicals allows us to anticipate that interactions between environmental chemicals (including dietary phytochemicals) and pharmaceuticals at the level of the CYP450 enzymes may be more prevalent than we have previously anticipated.

The normal distribution

The normal distribution, often referred to as the Gaussian distribution, and at other times, the bell curve, takes its name from the prodigious German mathematician Carl Friedrich Gauss (1777-1855), who discovered it while studying the distribution of measurement errors in astronomy.

It is something we take very much for granted in clinical and biomedical research. It is certainly something inherently useful in being able to group our observable data, and to be able to describe a central tendency that can be used to represent groups of subjects or patients. Another way of looking at the normal distribution of data is to do a probit analysis. Here is an example of the apparent normality in the frequency distribution as applied to the CYP1A2 metabolic ratio in a Chinese population. Under these circumstances, the probit plot approximates linearity.

Frequency and probit distribution of CYP1A2 activity in a Chinese population as indicated by plasma log-transformed 1,7-dimethylxanthine/caffeine [lg(17X/137X)] ratios (n = 419).Chen et al, Clinical Pharmacology & Therapeutics 78, 249-259 (September 2005)

In this instance however, the normality of the distribution hides a plethora of heterogeneity as the CYP1A2 gene is highly polymorphic, and the authors in this study reports that the G–3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.

In understanding diversity of human drug response, understanding 'normality' is an important starting point, but we need to look beyond this. Normality can work against us.