**2. Single-gene pharmacokinetics disorders**

#### **2.1 Pseudocholinesterase deficiency**

Pseudocholinesterase is a plasma enzyme produced in the liver that is responsible for the metabolism of common muscle relaxants, including succinylcholine and mivacurium [25]. The inherited form of the enzyme transfers in an autosomal recessive manner. Patients with defective inherited forms of pseudocholinesterase (heterozygotes and homozygotes) present with prolonged muscular paralysis. Acquired pseudocholinesterase deficiency can develop in a variety of diseases or as a side effect of certain medications [26]. Pseudocholinesterase deficiency can be induced by malnutrition, pregnancy and the postpartum period, burns, liver illness, renal disease, cancer, infections, and medications such as steroids and cytotoxic agents [27]. Both acquired and hereditary defects are considered uncommon. Caucasian males of European origin, as well as Alaskan Native tribes, have the highest frequency of pseudocholinesterase deficiency [28]. In pseudocholinesterase-deficient patients, there is no particular therapy for neuromuscular paralysis; nevertheless, respiratory assistance with mechanical ventilation can be provided until the neuromuscular blockade is resolved [29]. Nondepolarizing neuromuscular blockers, such as atracurium, rocuronium, and vecuronium, are indicated for those with pseudocholinesterase deficiency. In addition, relatives of those who have been diagnosed with pseudocholinesterase deficiency are advised to get tested for the condition [30].

#### **2.2 Acute intermittent porphyria**

Acute intermittent porphyria (AIP) is a pharmacogenetic disease caused by a porphyrin metabolic defect characterized by a lack of porphobilinogen deaminase and a rise in the activity of delta-aminolevulinic acid synthase—two essential enzymes required for heme production [31]. Patients may have stomach discomfort, vomiting, muscular weakness, constipation, and neuropsychiatric symptoms during an episode. Clinical episodes are produced by many drugs (including barbiturates, antiseizure drugs, and sulfonamide antibiotics), hormones, and dietary variables, all of which induce hepatic delta-aminolevulinic acid synthase [32].

The most accurate approach for confirming AIP in patients and their symptom-free relatives is DNA analysis. The hydroxymethylbilane synthase (HMBS) gene is directly sequenced to discover a mutation in the proband as well as asymptomatic gene carriers among family members [33]. The sensitivity of the mutation analysis ranges from 90–100%. So far, 391 mutations in the HMBS gene have been reported. Thus, DNA testing in a family's index case may be more difficult and time-consuming, but mutation analysis thereafter may quickly identify numerous family members at risk [34].

Heme infusions are frequently used to reduce the intensity and frequency of recurring episodes. The goal of this treatment is to significantly lower the level of porphyrin precursors in the blood. Most individuals react effectively, although longterm therapy may lead to exogenic heme dependency. As a result, a patient's heme need may grow from monthly to twice-weekly infusions, making treatment discontinuation difficult due to significant porphyric symptoms. The use of heme preparations on a regular basis might cause thrombotic problems in the superficial veins, necessitating the use of a permanent central venous catheter [35]. Furthermore, long-term heme therapy might result in iron excess and hemosiderosis, which can cause organ damage. Hepatopathy, heart failure and endocrinopathies may arise as a result of the disease progressing. Iron burden in organs is shown by computed tomography (CT) or magnetic resonance imaging (MRI) [36]. Venesections are generally unpopular, although iron chelates can help. Preventative actions can be taken if family members are tested to determine whether they are genetic carriers. Symptomatic treatment, a high carbohydrate diet, and intravenous hematin injection are all used to treat attacks [37].

#### **2.3 Drug acetylation deficiency**

N-acetyl transferase (NATS) activities in human hepatic drug metabolizing enzymes have previously been identified as a source of inter-individual heterogeneity in drug metabolism [38]. The liver's cytochrome P450 enzymes are primarily responsible for phase I oxidation, whereas phase 2 conjugations include glucuronidation, sulfation, and acetylation [39]. Two genes (NAT 1) and (NAT 2) are now known to control N-acetyl transferase (NAT), with NAT 2 A and B accounting for clinically significant metabolic variance [40].

Caffeine, isoniazid, nitrazepam, and sulfonamides are among the many common medications that are acetylated. Aromatic and heterocyclic amines are also carcinogenic, which has led to the theory that NAT genotypes are linked to cancer risk. Individuals can be divided into two groups after receiving sulfamethazine, caffeine, or another marker drug and having plasma and urine drug concentrations measured after a standard time interval: fast acetylators with only low concentrations of the parent drug remaining in the blood and slow acetylators with much higher concentrations of the parent drug remaining in the blood [41]. The frequency of fast and slow

*Interplay between Pharmacokinetics and Pharmacogenomics DOI: http://dx.doi.org/10.5772/intechopen.108407*

acetylators varies by ethnicity; Caucasian and Negro populations have almost equal numbers of fast and slow acetylators, whereas Oriental races have over 90% quick acetylators. The slow acetylator phenotype predominates among Arab people in Asia (e.g., Saudi Arabia and the United Arab Emirate) [42, 43] and North Africa (e.g., Egypt and Morocco) [40, 44].

### **3. Genetic variants affecting pharmacokinetics**

Genetic variation in drug-metabolizing enzymes and/or drug transporter genes might impact drug exposure in terms of PK key parameters, such as maximum drug concentration (Cmax) and area under the curve (AUC) [45]. These differences can affect a patient's loading dose, maintenance dose, dosing interval, and as a result, medication response and safety [46, 47].

#### **3.1 Pharmacogenomics of drug-metabolizing enzymes**

In the last decade, technical advancements in gene scanning and gene variant identification have substantially increased our understanding of the function of pharmacogenetics in drug metabolism [48, 49]. The number of genetic variants identified for genes coding for drug-metabolizing enzymes (DMEs) considerably increased in the early 2000s and continues to increase. Variation in drug metabolism and drug response can be caused by temporary factors, such as transient enzyme inhibition and induction, or by permanent causes, such as genetic mutation, gene deletion, or amplification among people of the same body weight and on the same medicine dosage. However, not all variants result in significant changes in enzyme activity. Genetic polymorphism can be associated with three phenotype classes based on drug metabolizing ability: the extensive drug metabolizer phenotype (EM) is found in the general population; the poor drug metabolizer phenotype (PM) is caused by mutation and/or deletion of both alleles and is linked to the accumulation of specific drug substrates; and gene amplification causes the UM phenotype, which results in increased drug metabolism [50]. The cytochrome P450 enzymes in families 1–3 mediate 70–90% of all phase I-dependent metabolism of available drugs [51]. The polymorphic forms of P450s are responsible for the development of approximately 86% of the reported adverse drug reactions (ADRs) of substrate drugs. Polymorphic enzymes (in particular, CYP2C9, CYP2C19, and CYP2D6) mediate around 40% of P450-mediated drug metabolism [52]. The major CYP450 forms that are important in human drug metabolism are shown in **Table 1**, together with their main substrates and the clinical consequences of the polymorphism.

#### **3.2 Pharmacogenomics of drug transporters**

The distribution of drug transporters in tissues key to pharmacokinetics, such as the intestine (absorption), blood-brain barrier (distribution), liver (metabolism), and kidneys (excretion), strongly suggests that genetic variation associated with changes in protein expression or function of these transporters may have a substantial impact on systemic drug exposure and toxicity [53]. In the last decade, a greater focus has been given to the impact of genetic variation in membrane transporters on the pharmacokinetics and toxicity of numerous therapeutic drugs [54]. While most transporter-related pharmacogenetic research has been related to classic genes


#### **Table 1.**

*CYP450 enzymes and related polymorphisms.*


#### **Table 2.**

*Drug transporters and related polymorphisms.*

encoding the outward-directed ATP-binding cassette (ABC) transporters, such as ABCB1 (P-glycoprotein), ABCC2 (MRP2), and ABCG2 (BCRP), more studies have been conducted in recent years evaluating genes encoding solute carriers (SLC) that mediate the cellular uptake of drugs, such as SLCO1B1 (OATP1B1) and SLC22A1 (OCT1) [55]. The main drug transporters are shown in **Table 2**, together with their main substrates and the clinical consequences of the polymorphism(s).
