**1.3.2 Distribution**

Being a lipo-soluble drug, methadone distributes widely in body tissues such as: liver, lung, kidney, gut, brain, and muscle with different distribution coefficients (Sawe, 1986). In opioid addicts, the volume of distribution at a steady state (Vss) ranged from 0.2 to 9.2 L/kg. On the other hand, in patients with chronic pain, Vss ranged from 1.71 to 5.34 L/kg (Inturrisi *et al*, 1990), though higher doses are usually given in such situations.

Methadone pharmacokinetic is described as a two-compartment model. Although there are wide differences in the reported clearance, the reported terminal half-life was estimated to range from 23-26 hours. Half-life depends also on the volume of distribution, making the explanations much more complicated and inconclusive (Eap *et al*, 2002; Li *et al*, 2008)

Methadone binds to plasma protein to a high degree of 86 percent, predominantly to acute α-glycoprotein (AAG) (Romach *et al*, 1981; Eap *et al*, 1990). AAG is an acute phase protein that exhibits significant variations in its plasma levels according to the physiological and/or pathological situation of the patient (Fournier *et al*, 2000; Yang *et al*, 2006; Mestriner *et al*, 2007). AAG levels are significantly increased in stress, leading to very low concentrations in the free fraction (fu) of methadone in cancer patients compared to healthy participants (Abramson, 1982; Gómez *et al*, 1995). Therefore, some studies have measured the concentration of AAG itself to study the impact of their concentration on methadone concentration and / or clinical outcomes. Rowland and Tozer (1995) have stated that 'after a

Variability of Plasma Methadone Concentration in Opiate Dependent

quality were assessed during the fourth week of the study.

**4. Results** 

Concentration (ng/ml)

0

Fig. 4.1. Daily Methadone Dose in the Study Patients

5

10

15

**Frequency**

20

25

30

Receiving Methadone: A Personalised Approach Towards Optimizing Dose 133

and sleeping quality, a subset of only 40 patients was further selected to participate. They were given a fixed 40 mg daily dose of methadone. Their withdrawal score and sleeping

One hundred and twenty eight patients were enrolled for this pilot study. Their doses were titrated appropriately as tolerated. However, at 12th month follow up, 88 patients out of the 128 participants fail to meet the inclusion criteria. Thus, in order to assess the efficacy of low dose methadone on the withdrawal effect and sleeping quality, a subset of only 40 patients was further selected to participate where they were given a fixed 40 mg daily dose of methadone. Daily dose averaged 57.2 mg (SD ± 22.7) (Table 4.1) and ranged from 20 to 160 mg per day (Figure 4.1). The corresponding plasma methadone concentration averaged 281.3 ng/ml (SD

Table 4.1. The Summary of Statistics, Daily Methadone Dose (mg) and Plasma Methadone

30 40 50 60 70 80 90 100 More

**Daily Dose**

Daily Dose,(mg) Plasma Concentration, (ng/ml)

± 567.9) (Table 4.1) and ranged from 0 to 4634 ng/ml (Figure 4.2, Figure 4.3)

Mean 57.19828 299.842 Standard Error 2.110416 57.0856 Median 50 180.8249 Standard Deviation 22.72988 582.1612 Sample Variance 516.6473 338911.6 Kurtosis 2.263482 39.11501 Skewness 1.040586 5.905204

rapid input of methadone, a decrease in fu will be indicated by an increase in Cp, because Vss is proportional to fu. On the other hand, Cu levels remain unchanged. So, if the Cu is the pharmacologically active concentration, a decrease in fu will not modify the maximum response. Thus, it has been suggested that AAG is significantly higher in patients exhibiting abstinence syndrome compared to those who are stable (Garrido *et al*, 2000) and AAG may contribute to the variations in methadone plasma levels.

Other factors that may contribute to variability include age and sex. It has been suggested that these factors may explain about 33 percent of the inter-individual variations in Vss. These parameters are found to be higher in females and they are directly related to weight (Wolff *et al*, 2000).

Furthermore, it has also been suggested that a time-dependent increase in methadone clearance may result from auto-induction of its own metabolism by *CYP3A4*, and the change in Vss may be due to up or down-regulation of AAG (Rostami-Hodjegan *et al*, 1999). Therefore, a time-dependent decrease in Vss may be associated with the observed timedependent increase in AAG.

#### **1.3.3 Elimination**

Generally, there is a huge inter-individual variability in methadone clearance that can reach up to 20 -100 folds in magnitude (Eap *et al*, 2002; Li *et al*, 2008). Methadone is eliminated by hepatic metabolism and renal excretion. It has been shown that at urinary pH of six and above, renal clearance accounts for four percent only. However, when urinary pH was lower than 6, the clearance of unchanged drug will be increased by 33 percent (Rostami-Hodjegan *et al*, 1999). It was concluded that, about 20-50 percent of the inter-individual variability can be explained by urinary excretion (KuKanich and Borum, 2008). With regard to hepatic clearance, methadone can be recognized as a drug with a low extraction ratio, 0.16 in MMT patients.
