PHARMACOKINETIC (ADME) PROFILING:

HYDROXYCHLOROQUINE (Anti-malarial)

Course Code: BIOC 8730

Submitted by: Team 19

Name Student ID

Sanchita Tiwari 110130151

Vidhi Makwana 110128626

Rishil Patel 110126264

Pari Patel 110094886

Aparna Krishna 110127839

Surbhi Bhingradiya 110126639

As a powerful tool for understanding how pharmaceuticals operate in the body and for directing decisions about
medication dose, safety, and efficacy, pharmacokinetic profiling (ADME) is essential to drug development,
clinical practice, and patient care.

ABSORPTION:
The Swiss ADME demonstrates that Hydroxychloroquine has a high GI absorption rate. The boiled egg
structure (Figs. 1 and 2) illustrates Hydroxychloroquine's inadequate passive gastronomical absorption (HIA).
After being taken orally, The body absorbs HCQ quickly and nearly entirely (via the gastrointestinal system, at
a rate of 70–80%) according to the article [3]. The Swiss ADME model (Fig. 2) predicts that The molecular
weight of hydrochloroquine is 335.87 g/mol, the value measured [8]. The literature study [1] states that the
likelihood of a molecule being absorbed into a cell increases with its size. Also, [5], as illustrated in Fig-3, all
the substances examined in the research adhere to Lipinski's rule of five without any deviations, demonstrating
their ability to induce a pharmacological response. According to the Swiss ADME website, Hydroxychloroquine
is moderately soluble in water, as indicated by PubChem. Also, according to [2], Higher water solubility is
achieved by synthesizing hydroxychloroquine, the hydroxyl derivative of chloroquine. Moreover, the drug's log
P (lipophilicity) of the drug is 3.58, which indicates that the drug is moderately lipophilic. (Figure-2) [8] which
is supported by [4]. HCQ, being lipophilic, can effortlessly penetrate cell membranes and gather within
intracellular vesicles, which encompass lysosomes, endosomes, and autophagosomes. Within these acidic
vesicles, HCQ disrupts the functionality of vesicular enzymes, such as proteases, by elevating the pH level. The
Swiss ADME reported the drug's bioavailability to be 0.55. (Fig. 2) [8] On the other hand, [6] found that
Hydroxychloroquine has a bioavailability of 0.7–0.8 and is quickly absorbed in the upper gastrointestinal
system.

DISTRIBUTION:
Hydroxychloroquine demonstrates high permeability across the blood-brain barrier (BBB), as predicted by
SWISS ADME, indicating its ability to enter the central nervous system quickly. This prediction aligns with its
placement in the "yolk" zone of the SWISS ADME Boiled Egg model, suggesting high gastrointestinal
absorption. The literature supports the substantial BBB penetration and GI absorption [7][8]. With an estimated
40% free fraction, Hydroxychloroquine exhibits significant binding to plasma proteins, potentially impacting its
volume of distribution (Vd), which ranges widely from 155 to 2,400 L [9][10]. Moreover, the SWISS ADME
predictions indicate that Hydroxychloroquine is not a substrate for P-gp using standard in vitro models, and
some evidence suggests it may have a moderate inhibitory effect on P-gp [11]. This could contribute to its
distribution characteristics, such as the improved bioavailability in the oral form of medications other than the
substrate of p-glycoprotein when taken with hydroxychloroquine [12]. Physicochemical characteristics like
lipophilicity and weak base nature may further influence Hydroxychloroquine's distribution [13]. Overall,
SWISS ADME predictions and literature support Hydroxychloroquine's significant pharmacokinetic profile and
distribution characteristics, including high BBB permeability, extensive tissue distribution, and susceptibility to
plasma protein binding.

METABOLISM:
In both the liver and the gut, CYP2D6 and CYP3A4 enzymes are principally responsible for the central
metabolism of Hydroxychloroquine. Furthermore, CYP2C19 metabolizes it mainly via N-dealkylation, which
produces active metabolites. Its metabolism is also somewhat aided by CYP2C9 and CYP1A2, which
synthesize hydroxylated metabolites [14]. Notably, desethylhydroxychloroquine (DHCQ) is the primary active
metabolite, with desethylchloroquine (DDCQ) serving as a secondary active metabolite [18]. The inactive
metabolite is desethylchloroquine (DCQ). Thus, monitoring for potential drug-drug interactions is crucial due to
the impact of Hydroxychloroquine and its metabolites on the metabolism and clearance of various drugs [17].
While it inhibits CYP2D6, it does not exhibit inhibitory effects on CYP3A4, CYP2C19, or CYP2C9, as
indicated in the accompanying table in the appendix (fig:4), aligning with predictions from Swiss ADME [16].
This inhibition pattern can alter the metabolism of concomitant drugs metabolized by these enzymes, potentially
elevating their levels and risk of toxicity. In a study of patients with a functional P450 2D6 metabolic pathway,
Hydroxychloroquine has improved metoprolol absorption. This is supported by notable increases in the area
under the plasma concentration-time curve (AUC, up 65 ± 5%) and the maximum plasma concentration of
metoprolol (up 72 ± 7%). The results indicate that Hydroxychloroquine probably prevents metoprolol from
breaking down, possibly inhibiting the P450 2D6 enzyme [15]. Furthermore, CYP2D6 autoinhibition and, by
extension, time-dependent nonlinear HCQ pharmacokinetics are called into doubt by the notion that HCQ
serves as both a substrate and an inhibitor of CYP2D6 [17].

EXCRETION:
The half-life of hydroxychloroquine is between 40 and 50 days after chronic oral use, increasing to 123.5 days
after a single 200 mg dose, indicating slower elimination [19]. It exhibits 50% plasma protein binding, with the
(R) enantiomer at 37% and (S) enantiomer at 64%, averaging 52% for the racemic mixture, binding to albumin
(29%) and alpha-1-acid glycoprotein (41%) [20]. Clearance is 96 mL/min, with renal clearance contributing 16-
30% of unchanged drug clearance (Drug bank). Food minimally affects Tmax but may increase Cmax and AUC
variably [21]. Renal excretion accounts for 40-50% [22], with 16-21% unchanged in the urine, 5% through the
skin, and 24-25% via feces [23]. Hydroxychloroquine's pharmacokinetics are linear [24].
 APPENDIX

Fig-1: Boiled Egg Structure of Hydroxychloroquine from Swiss ADME

Fig-2: Pharmacokinetics Parameters of Hydroxychloroquine from Swiss ADME

 Fig-3: Hydroxychloroquine Likeness [8]

Fig-4: Hydroxychloroquine metabolized by CYPs [16]

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